PROCESSES FOR THE PREPARATION OF (3S,4R)-3-ETHYL-4-(3H-IMIDAZO[1,2-a]PYRROLO[2,3-e]-PYRAZIN-8-YL)-N-(2,2,2-TRIFLUOROETHYL)PYRROLIDINE-1-CARBOXAMIDE AND SOLID STATE FORMS THEREOF

ABSTRACT

The present disclosure relates to processes for preparing (3S,4R)-3-ethyl-4-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, solid state forms thereof, and corresponding pharmaceutical compositions, methods of treatment (including treatment of rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis), kits, methods of synthesis, and products-by-process.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/656,237, filed Oct. 17, 2019, which is a continuation of U.S. patentapplication Ser. No. 15/891,012, filed Feb. 7, 2018, which is acontinuation of U.S. patent application Ser. No. 15/295,561, filed Oct.17, 2016, and which claims the benefit of U.S. Provisional ApplicationNo. 62/242,797, filed Oct. 16, 2015; and claims the benefit of U.S.Provisional Application No. 62/267,672, filed Dec. 15, 2015; and claimsthe benefit of U.S. Provisional Application No. 62/301,537, filed Feb.29, 2016; and claims the benefit of U.S. Provisional Application No.62/352,380, filed Jun. 20, 2016; all of which are herein incorporated byreference in their entirety.

FIELD OF THE INVENTION

The present disclosure relates to: (a) processes for the preparation of(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(referred to herein as “Compound 1”), (b) intermediates used in thepreparation of Compound 1 and processes for preparing the intermediates;(c) solid state forms of Compound 1, (d) pharmaceutical compositionscomprising one or more solid state forms of Compound 1, and, optionally,one or more additional therapeutic agents; (e) methods of treating Januskinase-associated conditions (including rheumatoid arthritis) byadministering one or more solid state forms of Compound 1 to a subjectin need thereof; (f) kits comprising a first pharmaceutical compositioncomprising a solid state form of Compound 1, and, optionally, a secondpharmaceutical composition comprising one or more additional therapeuticagents, (g) methods for the preparation of solid state forms of Compound1; and (h) solid state forms of Compound 1 prepared in accordance withsuch methods.

BACKGROUND OF THE INVENTION

(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(“Compound 1”) was first disclosed in International ApplicationWO2011/068881A1, which is herein incorporated by reference in itsentirety. The compound has activity as a Janus kinase (“JAK”) inhibitor,particularly as a JAK-1 inhibitor. Clinical trials are ongoing toevaluate the use of the compound to treat rheumatoid arthritis.

The isolation and commercial-scale preparation of a solid state form ofCompound 1 and corresponding pharmaceutical formulations havingacceptable solid state properties (including chemical stability, thermalstability, solubility, hygroscopicity, and/or particle size), compoundmanufacturability (including yield, impurity rejection duringcrystallization, filtration properties, drying properties, and millingproperties), and formulation feasibility (including stability withrespect to pressure or compression forces during tableting) present anumber of challenges that are discussed in greater detail below.Accordingly, there is a current need for one or more solid state formsof Compound 1 that have an acceptable balance of these properties andcan be used in the preparation of pharmaceutically acceptable soliddosage forms.

Additionally, currently known processes for the preparation of Compound1 involve the use of particularly hazardous reagents, such astrimethylsilyldiazomethane or diazomethane, and do not produce acrystalline product. There is thus also a need for a process forpreparing Compound 1, and pharmaceutically acceptable salts thereof,that avoids the use of particularly hazardous reagents, and can producea crystalline product and crystalline intermediates.

Additionally, sustained peak plasma concentrations can theoretically beachieved by means of sustained release matrix systems. However, whensuch systems are made of hydrophilic polymers, such as HPMC, they seldomprovide pH independent drug release of pH-dependent soluble drugs, andthey are normally incapable of attaining zero-order release except forpractically insoluble drugs. Unexpectedly, is has been discovered thatwhen tartaric acid is used as a pH-modifier in such a system, it allowsCompound 1 to be released at a steady rate regardless of the pH of theenvironment.

In an unexpected finding, it was discovered that as a tablet containingthe hydrophilic polymer matrix system erodes, Compound 1 reacts with theHPMC, creating a thicker gel layer which slows the release of Compound 1from the tablet. The resulting gel layer provided an environmentsuitable for Compound 1 to dissolve.

Axial spondyloarthritis (axSpA) encompasses a spectrum of inflammatoryinvolvement of the axial skeleton. Based on the Assessment ofSpondyloArthritis International Society (ASAS) axSpA criteria, thedisease can be further divided into 2 categories by radiographicfindings: ankylosing spondylitis (AS), and an “early” form of axial SpA,referred to as non-radiographic axial spondyloarthritis (nr-axSpA).Patients with nr-axSpA and AS share common epidemiological, genetic, andclinical disease characteristics, including with regard to diseaseactivity, and similar response to treatment. See, e.g., Poddubnyy andSieper, Curr Opin Rheumatol. (2014) 26:377-383.

Per international treatment recommendations, nonsteroidalanti-inflammatory drugs (NSAIDs) are the first-line therapy in axSpA.See, e.g., van der Heijde D et al., Ann Rheum Dis. (2017) 76:978-991;Ward et al., Arthritis Rheumatol. (2016) 68:282-298. After failure oftwo NSAIDs given over a maximum of four weeks, biologicdisease-modifying anti-rheumatic drugs (bDMARDs) are the nextrecommended treatment option. In axSpA, conventional syntheticdisease-modifying anti-rheumatic drugs (csDMARDs) and long-termcorticosteroids are not efficacious and therefore not recommended fortreatment of axial symptoms. See, e.g., van der Heijde D et al., AnnRheum Dis. (2017) 76:978-991. Furthermore, only approximately 45% to 50%of patients show an Assessment of SpondyloArthritis InternationalSociety 40 (ASAS40) response and only approximately 15% to 20% achieve astate of remission in biologic-naïve patients, and response rates areeven less in axSpA patients who had an inadequate response to bDMARDs.See, e.g., Sieper and Poddubnyy. Lancet (2017) 390:73-84; Sieper et al.,Ann Rheum Dis. (2017) 76:571-592; Rudwaleit et al., Arthritis Res Ther.(2010) 12:R117; Deodhar et al., Arthritis Rheumatol. (2019) 71:599-611.To date, other than NSAIDs, there have been no oral targeted therapiesapproved for the treatment of ankylosing spondylitis (AS) ornon-radiographic axSpA.

Psoriatic Arthritis (PsA) is a chronic systemic inflammatory diseaseclassified as a sub-type of spondyloarthritis (SpA) and characterized bythe association of arthritis and psoriasis. The course of PsA is usuallycharacterized by flares and remissions. Left untreated, patients withPsA can have persistent inflammation, progressive joint damage,disability, and a reduced life expectancy. Initial treatment of themusculoskeletal symptoms is composed of nonsteroidal anti-inflammatorydrugs (NSAIDs) and local corticosteroid injections, while topicaltherapies are used for the initial treatment of psoriasis. For subjectswho experience lack of efficacy or toxicity with these measures,systemic therapy with non-biologic disease modifying anti-rheumaticdrugs (non-biologic DMARDs) (e.g., methotrexate [MTX], leflunomide[LEF], sulfasalazine [SSZ]) and ciclosporin A, followed by anti-tumornecrosis factor (TNF) therapy in subjects who do not respond adequately,is recommended. Other biologic therapies (e.g., IL-12/23 or IL-17inhibitors) are also recommended as alternatives to anti-TNF inhibitorsin selected PsA subjects. See, e.g., Gossec et al., Ann Rheum Dis.(2016) 75:499-510; Coates et al., Arthritis Rheumatol. (2016)68:1060-71. However, despite the beneficial results achieved withcurrently available biologic agents, approximately 40% of patients donot have at least 20% improvement in American College of Rheumatology(ACR) scores and only 58% to 61% of patients with PsA who receive themare able to achieve clinical remission after 1 year of treatment, withonly approximately 43% achieving sustained remission for at least 1year. See, e.g., Gossec et al., Ann Rheum Dis. (2016) 75:499-510;Alamanos et al., J Rheumatol. (2003) 30:2641-2644; Savolainen et al., JRheumatol. (2003) 30:2460-8; Sandborn, Dig Dis. (2010) 28:536-42; Saberet al., Arthritis Res Therapy (2010) 12: R94; Perrotta et al., JRheumatol. (2016) 43:350-5.

Thus, there continues to remain a clear medical need for additionaltherapeutic options for the treatment of non-radiographic axialspondyloarthritis (nr-axSpA), ankylosing spondylitis (AS), psoriaticarthritis (PsA), and psoriasis (PsO), including PsO as a skinmanifestation of PsA.

SUMMARY OF THE INVENTION

In another aspect, the present disclosure relates to pharmaceuticalcompositions comprising one or more solid state forms of Compound 1,and, optionally, one or more additional therapeutic agents.

In another aspect, the present disclosure relates to methods of treatinga JAK-associated condition (such as rheumatoid arthritis) in a humansubject suffering from or susceptible to such a condition comprisingadministering to the subject a therapeutically effective amount of asolid state form of Compound 1. In another aspect, the disclosurerelates to a pharmaceutical composition comprising a therapeuticallyeffective amount of a solid state form of Compound 1 as described in thepresent disclosure, for use in treatment of a JAK-associated condition(such as rheumatoid arthritis) in a subject, particularly in a humansubject suffering from or susceptible to the condition.

In another aspect, the present disclosure relates to methods of treatingrheumatoid arthritis, wherein the term “rheumatoid arthritis” includesjuvenile rheumatoid arthritis, juvenile idiopathic arthritis, ankylosingspondylitis disease. Sjogren's syndrome, psoriatic arthritis.

In another aspect, the present disclosure relates to methods of treatinginflammatory bowel disease, wherein the term “inflammatory boweldisease” includes Crohn's disease, pediatric Crohn's disease andulcerative colitis.

In another aspect, the present disclosure relates to a method oftreating a condition selected from the group consisting of rheumatoidarthritis, juvenile idiopathic arthritis, Crohn's disease, ulcerativecolitis, psoriasis, plaque psoriasis, nail psoriasis, psoriaticarthritis, ankylosing spondylitis, alopecia areata, hidradenitissuppurativa, atopic dermatitis and systemic lupus erythematosus in ahuman subject suffering from or susceptible to such a condition, themethod comprising administering to the subject a therapeuticallyeffective amount a solid state form of Compound 1. In another aspect,the disclosure relates to a pharmaceutical composition comprising atherapeutically effective amount of a solid state form of Compound 1 asdescribed in the present disclosure, for use in treatment of a conditionselected from the group consisting of rheumatoid arthritis, juvenileidiopathic arthritis, Crohn's disease, ulcerative colitis, psoriasis,plaque psoriasis, nail psoriasis, psoriatic arthritis, ankylosingspondylitis, alopecia areata, hidradenitis suppurativa, atopicdermatitis, and systemic lupus erythematosus in a subject, particularlyin a human subject suffering from or susceptible to the condition.

In another aspect, the present disclosure relates to methods of treatinga JAK-associated condition (such as rheumatoid arthritis) in a humansubject suffering from or susceptible to such a condition comprisingadministering to the subject a solid state form of Compound 1, incombination with one or more additional therapeutic agents (e.g., atherapeutic agent for treating rheumatoid arthritis that is not a JAKinhibitor). In another aspect, the disclosure relates to apharmaceutical composition comprising a solid state form of Compound 1,as described in the present disclosure, in combination with one or moreadditional therapeutic agents (e.g., a therapeutic agent for treatingrheumatoid arthritis that is not a JAK inhibitor), for use in treatmentof a JAK-associated condition (such as rheumatoid arthritis) in asubject, particularly in a human subject suffering from or susceptibleto the condition.

In another aspect, the present disclosure relates to a method oftreating moderate to severely active rheumatoid arthritis, the methodcomprising administering a therapeutically effective amount of Compound1 in one or more forms as disclosed herein to a subject suffering fromor susceptible to the condition. In a particular aspect, such a methodmay comprise administering 7.5 mg once daily or 15 mg once daily, or 30mg once daily, or 45 mg once daily of the Compound 1, in one or moreforms as disclosed herein, to the subject. In this or another particularaspect, the subject may be administered the Compound 1 in Freebase FormC. In this or yet another particular aspect, the subject may have aninadequate response to methotrexate. In this or yet another particularaspect, the subject may have an inadequate response to biologicsmedicines approved for rheumatoid arthritis. In this or yet anotherparticular aspect, the subject may have not previously been administeredbiologics medicines approved for rheumatoid arthritis.

In another aspect, the present disclosure relates to a method oftreating an adult subject having moderate to severely active rheumatoidarthritis, the method comprising administering to the subject: a) about7.5 mg of Compound 1 freebase, or a pharmaceutically acceptable saltthereof, or a crystalline hydrate or a crystalline anhydrate of Compound1 in an amount sufficient to deliver to the subject about 7.5 mg ofCompound 1 freebase equivalent; or b) about 15 mg of Compound 1freebase, or a pharmaceutically acceptable salt thereof, or acrystalline hydrate or a crystalline anhydrate of Compound 1 in anamount sufficient to deliver to the subject about 15 mg of Compound 1freebase equivalent; or c) about 30 mg of Compound 1 freebase, or apharmaceutically acceptable salt thereof, or a crystalline hydrate or acrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 30 mg of Compound 1 freebase equivalent; or d)about 45 mg of Compound 1 freebase, or a pharmaceutically acceptablesalt thereof, or a crystalline hydrate or a crystalline anhydrate ofCompound 1 in an amount sufficient to deliver to the subject about 45 mgof Compound 1 freebase equivalent. In one embodiment, the presentdisclosure is directed to a pharmaceutical composition for use intreating an adult subject having moderate to severely active rheumatoidarthritis, the use comprising administering the pharmaceuticalcomposition to the subject, wherein the pharmaceutical compositioncomprises a) about 7.5 mg of Compound 1 freebase, or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or a crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 7.5 mg of Compound 1 freebase equivalent; or b) about 15mg of Compound 1 freebase, or a pharmaceutically acceptable saltthereof, or a crystalline hydrate or a crystalline anhydrate of Compound1 in an amount sufficient to deliver to the subject about 15 mg ofCompound 1 freebase equivalent; or c) about 30 mg of Compound 1freebase, or a pharmaceutically acceptable salt thereof, or acrystalline hydrate or a crystalline anhydrate of Compound 1 in anamount sufficient to deliver to the subject about 30 mg of Compound 1freebase equivalent; or d) about 45 mg of Compound 1 freebase, or apharmaceutically acceptable salt thereof, or a crystalline hydrate or acrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 45 mg of Compound 1 freebase equivalent.

In another embodiment, the present disclosure relates to a method oftreating structural damage associated with rheumatoid arthritis in anadult subject, the method comprising administering to the subject: a)about 7.5 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 7.5 mg per day of Compound 1 freebase equivalent; or b)about 15 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 15 mg per day of Compound 1 freebase equivalent; or c)about 30 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg per day of Compound 1 freebase equivalent; or d)about 45 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 45 mg per day of Compound 1 freebase equivalent; such thatthe structural damage in the adult subject is inhibited or lessened. Inone embodiment, the disclosure relates to a pharmaceutical compositionfor use in treating structural damage associated with rheumatoidarthritis in an adult subject, the use comprising administering thepharmaceutical composition to the subject, wherein the pharmaceuticalcomposition comprises: a) about 7.5 mg per day of Compound 1 freebase ora pharmaceutically acceptable salt thereof, or a crystalline hydrate orcrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 7.5 mg per day of Compound 1 freebase equivalent;or b) about 15 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 15 mg per day of Compound 1 freebase equivalent; or c)about 30 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg per day of Compound 1 freebase equivalent; or d)about 45 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 45 mg per day of Compound 1 freebase equivalent; such thatthe structural damage in the adult subject is inhibited or lessened.

In another aspect, the disclosure is directed to a method of treatingmoderate to severely active rheumatoid arthritis in an adult subject,the method comprising administering to the subject: a) about 7.5 mg perday of Compound 1 freebase or a pharmaceutically acceptable saltthereof, or a crystalline hydrate or crystalline anhydrate of Compound 1in an amount sufficient to deliver to the subject about 7.5 mg per dayof Compound 1 freebase equivalent; or b) about 15 mg per day of Compound1 freebase or a pharmaceutically acceptable salt thereof, or acrystalline hydrate or crystalline anhydrate of Compound 1 in an amountsufficient to deliver to the subject about 15 mg per day of Compound 1freebase equivalent; or c) about 30 mg per day of Compound 1 freebase ora pharmaceutically acceptable salt thereof, or a crystalline hydrate orcrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 30 mg per day of Compound 1 freebase equivalent; ord) about 45 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 45 mg per day of Compound 1 freebase equivalent; whereinthe subject has symptoms selected from the group consisting of at least6 swollen joints, at least 6 tender joints, and combinations thereofprior to treating. In one embodiment, the disclosure is directed to apharmaceutical composition for use in treating moderate to severelyactive rheumatoid arthritis in an adult subject, the use comprisingadministering the pharmaceutical composition to the subject, wherein thepharmaceutical composition comprises: a) about 7.5 mg per day ofCompound 1 freebase or a pharmaceutically acceptable salt thereof, or acrystalline hydrate or crystalline anhydrate of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg per day of Compound 1freebase equivalent; or b) about 15 mg per day of Compound 1 freebase ora pharmaceutically acceptable salt thereof, or a crystalline hydrate orcrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 15 mg per day of Compound 1 freebase equivalent; orc) about 30 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg per day of Compound 1 freebase equivalent; or d)about 45 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 45 mg per day of Compound 1 freebase equivalent; whereinthe subject has symptoms selected from the group consisting of at least6 swollen joints, at least 6 tender joints, and combinations thereofprior to treating.

In another aspect, the disclosure is directed to a method of reducingsigns and symptoms of rheumatoid arthritis in an adult subject withmoderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject: a) about 7.5 mg per day ofCompound 1 freebase or a pharmaceutically acceptable salt thereof, or acrystalline hydrate or crystalline anhydrate of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg of Compound 1 freebaseequivalent; or b) about 15 mg per day of Compound 1 freebase or apharmaceutically acceptable salt thereof, or a crystalline hydrate orcrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 15 mg of Compound 1 freebase equivalent; or c)about 30 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg of Compound 1 freebase equivalent; or d) about 45 mgper day of Compound 1 freebase or a pharmaceutically acceptable saltthereof, or a crystalline hydrate or crystalline anhydrate of Compound 1in an amount sufficient to deliver to the subject about 45 mg ofCompound 1 freebase equivalent. In one embodiment, the disclosure isdirected to a pharmaceutical composition for use in reducing signs andsymptoms of rheumatoid arthritis in an adult subject with moderately toseverely active rheumatoid arthritis, the use comprising administeringthe pharmaceutical composition to the subject, wherein thepharmaceutical composition comprises: a) about 7.5 mg per day ofCompound 1 freebase or a pharmaceutically acceptable salt thereof, or acrystalline hydrate or crystalline anhydrate of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg of Compound 1 freebaseequivalent; or b) about 15 mg per day of Compound 1 freebase or apharmaceutically acceptable salt thereof, or a crystalline hydrate orcrystalline anhydrate of Compound 1 in an amount sufficient to deliverto the subject about 15 mg of Compound 1 freebase equivalent; or c)about 30 mg per day of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof, or a crystalline hydrate or crystallineanhydrate of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg of Compound 1 freebase equivalent; or d) about 45 mgper day of Compound 1 freebase or a pharmaceutically acceptable saltthereof, or a crystalline hydrate or crystalline anhydrate of Compound 1in an amount sufficient to deliver to the subject about 45 mg ofCompound 1 freebase equivalent.

In another aspect, the present disclosure relates to kits comprising oneor more pharmaceutical compositions comprising a solid state form ofCompound 1. The kit optionally can comprise another pharmaceuticalcomposition comprising one or more additional therapeutic agents and/orinstructions, for example, instructions for using the kit.

In another aspect, the present disclosure relates to methods for thepreparation of a solid state form of Compound 1.

In another aspect, the present disclosure relates to solid state formsof Compound 1 prepared in accordance with such methods.

In another aspect, the present disclosure relates to a method oftreating an adult subject having moderate to severely active rheumatoidarthritis, the method comprising administering to the subject about 7.5mg, or about 15 mg, or about 30 mg, or about 45 mg of Compound 1freebase, or a crystalline hydrate of Compound 1 in an amount sufficientto deliver to the subject about 7.5 mg, or about 15 mg, or about 30 mg,or about 45 mg of Compound 1 freebase equivalent. In this or anotherparticular aspect, the hydrate may be a hemihydrate. In this or anotheraspect, the hemihydrate may be Freebase Hydrate Form C. In this or yetanother particular aspect, the subject may have an inadequate responseor tolerance to one or more disease-modifying antirheumatic drugs(DMARDS), such as methotrexate. In this or yet another particularaspect, the subject may have not previously been administered DMARDS. Inthis or yet another particular aspect, the subject may further beadministered one or more DMARD.

In another aspect, the present disclosure relates to a method oftreating structural damage associated with rheumatoid arthritis in anadult subject, the method comprising administering to the subject about7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day ofCompound 1 freebase or a crystalline hydrate of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg, or about 15 mg, orabout 30 mg, or about 45 mg per day of Compound 1 freebase equivalent,such that the structural damage in the adult subject is inhibited orlessened. In this or another particular aspect, the hydrate may be ahemihydrate. In this or another aspect, the hemihydrate may be FreebaseHydrate Form C.

In another aspect, the present disclosure relates to a method oftreating moderate to severely active rheumatoid arthritis in an adultsubject, the method comprising administering to the subject about 7.5mg, or about 15 mg, or about 30 mg, or about 45 mg per day of Compound 1freebase or a crystalline hydrate of Compound 1 in an amount sufficientto deliver to the subject about 7.5 mg, or about 15 mg, or about 30 mg,or about 45 mg per day of Compound 1 freebase equivalent, wherein thesubject has symptoms selected from the group consisting of at least 6swollen joints, at least 6 tender joints, and combinations thereof priorto treating. In this or another particular aspect, the hydrate may be ahemihydrate. In this or another aspect, the hemihydrate may be FreebaseHydrate Form C.

In another aspect, the present disclosure relates to a method ofreducing signs and symptoms of rheumatoid arthritis in an adult subjectwith moderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 7.5 mg per day of Compound1 freebase or a crystalline hydrate of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg of Compound 1 freebaseequivalent. In this or another particular aspect, the hydrate may be ahemihydrate. In this or another aspect, the hemihydrate may be FreebaseHydrate Form C.

In another aspect, the present disclosure relates to a method ofreducing signs and symptoms of rheumatoid arthritis in an adult subjectwith moderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 15 mg per day of Compound1 freebase or a crystalline hydrate of Compound 1 in an amountsufficient to deliver to the subject about 15 mg of Compound 1 freebaseequivalent. In this or another particular aspect, the hydrate may be ahemihydrate. In this or another aspect, the hemihydrate may be FreebaseHydrate Form C.

In another aspect, the present disclosure relates to a method ofreducing signs and symptoms of rheumatoid arthritis in an adult subjectwith moderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 30 mg per day of Compound1 freebase or a crystalline hydrate of Compound 1 in an amountsufficient to deliver to the subject about 30 mg of Compound 1 freebaseequivalent. In this or another particular aspect, the hydrate may be ahemihydrate. In this or another aspect, the hemihydrate may be FreebaseHydrate Form C.

In another aspect, the present disclosure relates to a method ofreducing signs and symptoms of rheumatoid arthritis in an adult subjectwith moderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 45 mg per day of Compound1 freebase or a crystalline hydrate of Compound 1 in an amountsufficient to deliver to the subject about 45 mg of Compound 1 freebaseequivalent. In this or another particular aspect, the hydrate may be ahemihydrate. In this or another aspect, the hemihydrate may be FreebaseHydrate Form C.

In another aspect, the present disclosure relates to a pharmaceuticalcomposition comprising a crystalline hydrate of Compound 1 and apharmaceutically acceptable carrier, wherein the composition comprisesthe crystalline hydrate in an amount sufficient to deliver about 7.5 mgof Compound 1 freebase equivalent. In this or another particular aspect,the hydrate may be a hemihydrate. In this or another aspect, thehemihydrate may be Freebase Hydrate Form C.

In another aspect, the present disclosure relates to a pharmaceuticalcomposition comprising a crystalline hydrate of Compound 1 and apharmaceutically acceptable carrier, wherein the composition comprisesthe crystalline hydrate in an amount sufficient to deliver about 15 mgof Compound 1 freebase equivalent. In this or another particular aspect,the hydrate may be a hemihydrate. In this or another aspect, thehemihydrate may be Freebase Hydrate Form C.

In another aspect, the present disclosure relates to a pharmaceuticalcomposition comprising a crystalline hydrate of Compound 1 and apharmaceutically acceptable carrier, wherein the composition comprisesthe crystalline hydrate in an amount sufficient to deliver about 30 mgof Compound 1 freebase equivalent. In this or another particular aspect,the hydrate may be a hemihydrate. In this or another aspect, thehemihydrate may be Freebase Hydrate Form C.

In another aspect, the present disclosure relates to a pharmaceuticalcomposition comprising a crystalline hydrate of Compound 1 and apharmaceutically acceptable carrier, wherein the composition comprisesthe crystalline hydrate in an amount sufficient to deliver about 45 mgof Compound 1 freebase equivalent. In this or another particular aspect,the hydrate may be a hemihydrate. In this or another aspect, thehemihydrate may be Freebase Hydrate Form C.

In another aspect, the present disclosure relates to a method oftreating an adult subject having moderate to severely active rheumatoidarthritis, the method comprising administering to the subject about 7.5mg, or about 15 mg, or about 30 mg, or about 45 mg of a crystallinehydrate of Compound 1. In this or another particular aspect, the hydratemay be a hemihydrate. In this or another aspect, the hemihydrate may beFreebase Hydrate Form C.

In another aspect, the present disclosure relates to a method oftreating structural damage associated with rheumatoid arthritis in anadult subject, the method comprising administering to the subject about7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg per day of acrystalline hydrate of Compound 1, such that the structural damage inthe adult subject is inhibited or lessened. In this or anotherparticular aspect, the hydrate may be a hemihydrate. In this or anotheraspect, the hemihydrate may be Freebase Hydrate Form C.

In another aspect, the present disclosure relates to a method oftreating moderate to severely active rheumatoid arthritis in an adultsubject, the method comprising administering to the subject about 7.5mg, or about 15 mg, or about 30 mg, or about 45 mg per day of acrystalline hydrate of Compound 1, wherein the subject has symptomsselected from the group consisting of at least 6 swollen joints, atleast 6 tender joints, and combinations thereof prior to treating. Inthis or another particular aspect, the hydrate may be a hemihydrate. Inthis or another aspect, the hemihydrate may be Freebase Hydrate Form C.

In another aspect, the present disclosure relates to a method ofreducing signs and symptoms of rheumatoid arthritis in an adult subjectwith moderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 7.5 mg, or about 15 mg, orabout 30 mg, or about 45 mg per day of a crystalline hydrate ofCompound 1. In this or another particular aspect, the hydrate may be ahemihydrate. In this or another aspect, the hemihydrate may be FreebaseHydrate Form C.

In another aspect, the present disclosure is directed to an extendedrelease formulation for oral administration comprising Compound 1 or apharmaceutically acceptable salt thereof, a hydrophilic polymer, and apH modifier, wherein the hydrophilic polymer, in contact with water,forms a gel layer that provides an environment suitable for Compound 1and the pH modifier to dissolve.

The present disclosure addresses the above needs and provides methodsfor treating axial spondyloarthritis (axSpA), including non-radiographicaxSpA (nr-axSpA) and ankylosing spondylitis (AS), and for treatingpsoriatic arthritis (PsA) and psoriasis (PsO), including PsO as a skinmanifestation of PsA.

The below recited Embodiments 1-77 set forth certain aspects of themethods as described herein.

Embodiment 1: In certain aspects, provided is a method of treatingactive ankylosing spondylitis (AS) in a subject in need thereof, themethod comprising orally administering to the subject once a day for atleast 14 weeks a dose of upadacitinib freebase, or a pharmaceuticallyacceptable salt thereof, in an amount sufficient to deliver 15 mg ofupadacitinib freebase equivalent, wherein the subject achieves anAssessment of SpondyloArthritis International Society 40 (ASAS40)response within 14 weeks of administration of the first dose.

Embodiment 2: The method of Embodiment 1, wherein when the method isused to treat a population of subjects, at least 10%, at least 15%, atleast 20%, at least 25%, at least 30%, at least 35%, at least 40%, or atleast 45% of the subjects in the treated population achieve an ASAS40response within 14 weeks of administration of the first dose. In certainembodiments of the method of Embodiment 1, wherein when the method isused to treat a population of subjects, a statistically significantpopulation of the subjects in the treated population achieves an ASAS40response within 14 weeks of administration of the first dose.

Embodiment 3: The method of Embodiment 1 or 2, wherein the subject orsubjects in the treated population suffering from active AS at baselinefurther achieve within 14 weeks of administration of the first dose atleast one result selected from the group consisting of:

-   -   a. improvement from baseline in Ankylosing Spondylitis Disease        Activity Score (ASDAS);    -   b. improvement from baseline in magnetic resonance imaging (MRI)        Spondyloarthritis Research Consortium of Canada (SPARCC) score        for spine (MRI-Spine SPARCC);    -   c. ASAS partial remission (PR);    -   d. Bath Ankylosing Spondylitis Disease Activity Index 50        (BASDAI50) response;    -   e. improvement from baseline in Bath Ankylosing Spondylitis        Functional Index (BASFI);    -   f. ASDAS low disease activity (LDA);    -   g. ASDAS inactive disease (ID);    -   h. ASDAS major improvement (MI); and    -   i. ASDAS clinically important improvement (CII).

In certain embodiments of the method of Embodiment 1 or 2, when themethod is used to treat a population of subjects, at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, or at least 45% of the subjects in the treated population achieveat least one of these results within 14 weeks of administration of thefirst dose. In other embodiments of the method of Embodiment 1 or 2,when the method is used to treat a population of subjects, astatistically significant population of subjects in the treatedpopulation achieves at least one result within 14 weeks ofadministration of the first dose.

Embodiment 4: The method of Embodiment 3, wherein the subject orsubjects in the treated population suffering from active AS at baselinefurther achieve within 14 weeks of administration of the first dose eachresult.

Embodiment 5: The method of any one of Embodiments 1-4, wherein thesubject or subjects in the treated population fulfill the 1984 modifiedNew York Criteria for ankylosing spondylitis at baseline.

Embodiment 6: The method of any one of Embodiments 1-5, wherein thesubject or subjects in the treated population fulfill the 2009 ASASclassification criteria at baseline.

Embodiment 7: The method of any one of Embodiments 1-6, wherein thesubject or subjects in the treated population meet at least one criteriaat baseline selected from the group consisting of:

-   -   a. a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)        score≥4;    -   b. an Ankylosing Spondylitis Disease Activity Score (ASDAS) of        ≥2.1; and    -   c. a Patient's Assessment of Total Back Pain (Total Back Pain        score) of ≥4 based on a 0-10 numerical rating scale.

Embodiment 8: The method of any one of Embodiments 1-7, wherein thesubject or subjects in the treated population are biologicdisease-modifying anti-rheumatic drug (bDMARD) naïve at baseline.

Embodiment 9: The method of any one of Embodiments 1-7, wherein thesubject or subjects in the treated population have had an inadequateresponse or intolerance to a biologic disease-modifying anti-rheumaticdrug (bDMARD) at baseline.

Embodiment 10: The method of Embodiment 9, wherein prior toadministration of the first dose, the subject or subjects in the treatedpopulation have been administered one bDMARD, and discontinued use ofthe bDMARD due to intolerance or lack of efficacy.

Embodiment 11: The method of Embodiment 10, wherein the bDMARD is atumor necrosis factor (TNF) inhibitor or an interleukin (IL)-17inhibitor.

Embodiment 12: The method of any one of Embodiments 1-11, wherein thesubject or subjects in the treated population have had an inadequateresponse or intolerance to at least two NSAIDs, intolerance to NSAIDS,and/or contraindication for NSAIDs at baseline.

Embodiment 13: In other aspects, provided is a method of treating activenon-radiographic axial spondyloarthritis in a subject in need thereof,the method comprising orally administering to the subject once a day forat least 14 weeks a dose of upadacitinib freebase, or a pharmaceuticallyacceptable salt thereof, in an amount sufficient to deliver 15 mg ofupadacitinib freebase equivalent, wherein the subject achieves an ASAS40response within 14 weeks of administration of the first dose. In certainembodiments, when the method is used to treat a population of subjects,at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, or at least 45% of the subjects in the treatedpopulation achieve an ASAS40 response within 14 weeks of administrationof the first dose. In certain embodiments, a statistically significantpopulation of subjects in the treated population achieve an ASAS40response within 14 weeks of administration of the first dose.

Embodiment 14: In yet other aspects, provided is a method of treatingactive non-radiographic axial spondyloarthritis in a subject in needthereof, the method comprising orally administering to the subject oncea day for at least 52 weeks a dose of upadacitinib freebase, or apharmaceutically acceptable salt thereof, in an amount sufficient todeliver 15 mg of upadacitinib freebase equivalent, wherein the subjectachieves an ASAS40 response within 52 weeks of administration of thefirst dose. In certain embodiments, when the method is used to treat apopulation of subjects, at least 10%, at least 15%, at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, or at least 45% ofthe subjects in the treated population achieve an ASAS40 response within52 weeks of administration of the first dose. In certain embodiments, astatistically significant population of subjects in the treatedpopulation achieves an ASAS40 response within 52 weeks of administrationof the first dose.

Embodiment 15: The method of Embodiment 13 or 14, wherein the subject orsubjects in the treated population fulfill at baseline the 2009 ASASclassification criteria for axial spondyloarthritis, but does not meetthe radiologic criteria of the 1984 modified New York criteria forankylosing spondylitis.

Embodiment 16: The method of Embodiment 13 or 14, wherein the subject orsubjects in the treated population meet at least one criteria atbaseline selected from the group consisting of:

-   -   a. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)        score of ≥4;    -   b. an Ankylosing Spondylitis Disease Activity Score (ASDAS) of        ≥2.1;    -   c. a Patient's Assessment of Total Back Pain (Total Back Pain        score) of ≥4 based on a 0-10 numerical rating scale; and    -   d. an objective sign of inflammatory activity selected from the        group consisting of:        -   i. an objective sign of active inflammation on MRI of            sacroiliac (SI) joints, and        -   ii. high-sensitivity C reactive protein>upper limit of            normal (ULN).

Embodiment 17: The method of any one of Embodiments 13-16, wherein thesubject or subjects in the treated population are bDMARD naïve atbaseline.

Embodiment 18: The method of any one of Embodiments 13-16, wherein thesubject or subjects in the treated population have had an inadequateresponse or intolerance to a bDMARD at baseline.

Embodiment 19: The method of Embodiment 18, wherein prior toadministration of the first dose, the subject or subjects in the treatedpopulation have been administered one bDMARD, and discontinued use ofthe bDMARD due to intolerance or lack of efficacy.

Embodiment 20: The method of Embodiment 19, wherein the bDMARD is atumor necrosis factor (TNF) inhibitor or an interleukin (IL)-17inhibitor.

Embodiment 21: The method of any one of Embodiments 13-20, wherein thesubject or subjects in the treated population have had an inadequateresponse or intolerance to at least 2 NSAIDs, has an intolerance toNSAIDS, and/or has a contraindication for NSAIDs at baseline.

Embodiment 22: The method of any one of Embodiments 13-21, wherein thesubject or subjects in the treated population achieve within 14 weeks ofadministration of the first dose at least one additional result selectedfrom the group consisting of:

-   -   a. improvement from baseline in Ankylosing Spondylitis Disease        Activity Score (ASDAS);    -   b. improvement from baseline in magnetic resonance imaging (MRI)        Spondyloarthritis Research Consortium of Canada (SPARCC) score        for SI joints (MRI-SI joints SPARCC);    -   c. ASAS partial remission (PR);    -   d. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)        50 response;    -   e. improvement from baseline in Bath Ankylosing Spondylitis        Functional Index (BASFI);    -   f. improvement from baseline in Ankylosing Spondylitis Quality        of Life (ASQoL);    -   g. improvement from baseline in ASAS Health Index (HI);    -   h. improvement from baseline in Maastricht Ankylosing        Spondylitis Enthesitis Score (MASES); and    -   i. improvement from baseline in Linear Bath Ankylosing        Spondylitis Metrology Index (BASMI_(lin)).

In certain embodiments of the method of any one of Embodiments 13-21,wherein when the method is used to treat a population of subjects, atleast 10/6, at least 15%, at least 20/6, at least 25%, at least 30%, atleast 35%, at least 40%, or at least 45% of the subjects in the treatedpopulation achieve at least one result within 14 weeks of administrationof the first dose. In certain embodiments of the method of any one ofEmbodiments 13-21, wherein when the method is used to treat a populationof subjects, a statistically significant population of subjects in thetreated population achieves at least one result within 14 weeks ofadministration of the first dose.

Embodiment 23: In yet other aspects, provided is a method of treatingactive psoriatic arthritis (PsA) in a subject in need thereof, themethod comprising orally administering to the subject once a day for atleast 12 weeks a dose of upadacitinib freebase, or a pharmaceuticallyacceptable salt thereof, in an amount sufficient to deliver 15 mg ofupadacitinib freebase equivalent, wherein the subject achieves anAmerican College of Rheumatology 20% (ACR20) response within 12 weeks ofadministration of the first dose.

Embodiment 24: In still yet other aspects, provided is a method oftreating active psoriatic arthritis (PsA) in a subject in need thereof,the method comprising orally administering to the subject once a day forat least 12 weeks a dose of upadacitinib freebase, or a pharmaceuticallyacceptable salt thereof, in an amount sufficient to deliver 30 mg ofupadacitinib free base equivalent, wherein the subject achieves anAmerican College of Rheumatology 20% (ACR20) response within 12 weeks ofadministration of the first dose.

Embodiment 25: The method of Embodiment 23 or 24, wherein when themethod is used to treat a population of subjects, at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, or at least 45% of the subjects in the treated population achievean ACR20 response within 12 weeks of administration of the first dose.In other embodiments of the method of Embodiment 23 or 24, when themethod is used to treat a population of subjects, a statisticallysignificant population of subjects in the treated population achieves anACR20 response within 12 weeks of administration of the first dose.

Embodiment 26: The method of any one of Embodiments 23-25, wherein thesubject or subjects in the treated population suffering from active PsAat baseline further achieve at least one result selected from the groupconsisting of:

-   -   a. improvement from baseline in Health Assessment        Questionnaire-Disability Index (HAQ-DI) within 12 weeks of        administration of the first dose;    -   b. achieve Static Investigator Global Assessment (sIGA) of        Psoriasis of 0 or 1 and at least a 2-point improvement from        baseline at within 16 weeks of administration of the first dose        (for subjects with baseline sIGA≥2);    -   c. achieve Psoriasis Area Severity Index (PASI) 75 response        within 16 weeks of administration of the first dose (for        subjects with ≥3% BSA psoriasis at baseline);    -   d. improvement from baseline in Sharp/van der Heijde Score (SHS)        within 24 weeks of administration of the first dose;    -   e. achieve Minimal Disease Activity (MDA) within 24 weeks of        administration of the first dose;    -   f. improvement from baseline in Leeds Enthesitis Index (LEI)        within 24 weeks of administration of the first dose, preferably        wherein the improvement is a resolution of enthesitis (LEI=0)        within 24 weeks of administration of the first dose (for        subjects with baseline presence of enthesitis (LEI>0));    -   g. achieve ACR 20 response within 12 weeks of administration of        the first dose (non-inferiority of upadacitinib vs adalimumab);    -   h. improvement from baseline in 36-Item Short Form Health Survey        (SF-36) within 12 weeks of administration of the first dose; and    -   i. improvement from baseline in Functional Assessment of Chronic        Illness Therapy-Fatigue (FACIT-F) Questionnaire within 12 weeks        of administration of the first dose.

In certain embodiments, wherein when the method of Embodiments 23-25 isused to treat a population of subjects, at least 10%, at least 15%, atleast 20%, at least 25%, at least 30%, at least 35%, at least 40%, or atleast 45% of the subjects in the treated population achieve at least oneresult within 14 weeks of administration of the first dose. In otherembodiments, wherein when the method of Embodiments 23-25 is used totreat a population of subjects, a statistically significant populationof subjects in the treated population achieve at least one result within14 weeks of administration of the first dose.

Embodiment 27: The method of Embodiment 26, wherein the subject orsubjects in the treated population suffering from active PsA at baselinefurther achieve each result.

Embodiment 28: The method of anyone of Embodiments 23-27, wherein thesubject or subjects in the treated population suffering from active PsAat baseline further achieve at least one result selected from the groupconsisting of:

-   -   a. ACR 20 response and superiority over adalimumab (40 mg every        other week) within 12 weeks of administration of the first dose;        and    -   b. improvement from baseline in Leeds Dactylitis Index (LDI)        within 24 weeks of administration of the first dose, preferably        wherein the improvement is a resolution of dactylitis (LDI=0)        within 24 weeks of administration of the first dose (for        subjects with baseline presence of dactylitis (LDI>0)).

In certain embodiments of Embodiment 28, wherein when the method is usedto treat a population of subjects, at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least45% of the subjects in the treated population achieve at least oneresult within 14 weeks of administration of the first dose. In otherembodiments of Embodiment 28, wherein when the method is used to treat apopulation of subjects, a statistically significant population ofsubjects in the treated population achieve at least one result within 14weeks of administration of the first dose.

Embodiment 29: The method of Embodiment 28, wherein the subject orsubjects in the treated population suffering from active PsA furtherachieve ACR 20 response and superiority over adalimumab (40 mg everyother week) within 12 weeks of administration of the first dose. Incertain embodiments of Embodiment 29, a statistically significantpopulation of subjects in the treated population achieves an ACR20response and superiority over adalimumab within 12 weeks ofadministration of the first dose. In certain embodiments of Embodiment29, at least 10%, at least 15%, at least 20%, at least 25%, at least30%, at least 35%, at least 40%, or at least 45% of the subjects in thetreated population achieve an ACR20 response and superiority overadalimumab within 12 weeks of administration of the first dose.

Embodiment 30: The method of Embodiment 29, wherein the subject orsubjects in the treated population suffering from active PsA are orallyadministered once a day for at least 12 weeks a dose of upadacitinibfreebase, or a pharmaceutically acceptable salt thereof, in an amountsufficient to deliver 30 mg of upadacitinib freebase equivalent.

Embodiment 31: The method of any one of Embodiments 23-30, wherein thesubject or subjects in the treated population achieve an ACR 50%response (ACR50) within 12 weeks of administration of the first dose. Incertain embodiments of Embodiment 31, a statistically significantpopulation of subjects in the treated population achieves an ACR50response within 12 weeks of administration of the first dose. In certainembodiments of Embodiment 31, at least 10%, at least 15%, at least 20%,at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%of subjects in the treated population achieve an ACR50 response within12 weeks of administration of the first dose.

Embodiment 32: The method of any one of Embodiments 23-30, wherein thesubject or subjects in the treated population achieve an ACR 70%response (ACR70) within 12 weeks of administration of the first dose. Incertain embodiments of Embodiment 32, a statistically significantpopulation of subjects in the treated population achieves an ACR70response within 12 weeks of administration of the first dose. In certainembodiments of Embodiment 32, at least 10%, at least 15%, at least 20%,at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%of the subjects in the treated population achieve an ACR70 responsewithin 12 weeks of administration of the first dose.

Embodiment 33: The method of any one of Embodiments 23-32, wherein thesubject or subjects in the treated population fulfill the ClassificationCriteria for Psoriatic Arthritis (CASPAR) criteria at baseline.

Embodiment 34: The method of claim of any one of Embodiments 23-33,wherein the subject or subjects in the treated population have at leastone criteria selected from the group consisting of ≥3 tender joints(based on 68 joint counts) and ≥3 swollen joints (based on 66 jointcounts) at baseline.

Embodiment 35: The method of Embodiment 34, wherein the subject orsubjects in the treated population have ≥5 tender joints (based on 68joint counts) and ≥5 swollen joints (based on 66 joint counts) atbaseline.

Embodiment 36: The method of any one of Embodiments 23-35, wherein thesubject or subjects in the treated population have at least one criteriaselected from the group consisting of ≥1 erosion on x-ray as determinedby central imaging review, and hs-CRP>laboratory defined upper limit ofnormal (ULN) at baseline.

Embodiment 37: The method of any one of Embodiments 23-36, wherein thesubject or subjects in the treated population have a diagnosis of activeplaque psoriasis, or the subject has a documented history of plaquepsoriasis at baseline.

Embodiment 38: The method of any one of Embodiments 23-36, wherein thesubject or subjects in the treated population have had an inadequateresponse or intolerance to at least one biologic disease-modifyinganti-rheumatic drug (bDMARD) at baseline.

Embodiment 39: The method of Embodiment 38, wherein the subject orsubjects in the treated population have discontinued all bDMARDs priorto administration of the first dose.

Embodiment 40: The method of any one of Embodiments 23-36, wherein thesubject or subjects in the treated population have had an inadequateresponse or intolerance to previous or concurrent treatment with atleast one non-biologic DMARD, or an intolerance to or contraindicationfor non-biologic DMARDs at baseline.

Embodiment 41: The method of any one of Embodiments 2340, wherein thesubject or subjects in the treated population have moderately toseverely active psoriatic arthritis at baseline.

Embodiment 42: In yet other aspects, provided is a method of treatingactive psoriasis in a subject in need thereof, the method comprisingorally administering to the subject once a day for at least 16 weeks adose of upadacitinib freebase, or a pharmaceutically acceptable saltthereof, in an amount sufficient to deliver 15 mg of upadacitinibfreebase equivalent, wherein the subject achieves a Psoriasis AreaSeverity Index (PASI) 75 response within 16 weeks of administration ofthe first dose.

Embodiment 43: In yet other aspects, provided is a method of treatingactive psoriasis in a subject in need thereof, the method comprisingorally administering to the subject once a day for at least 16 weeks adose of upadacitinib freebase, or a pharmaceutically acceptable saltthereof, in an amount sufficient to deliver 30 mg of upadacitinibfreebase equivalent, wherein the subject achieves a Psoriasis AreaSeverity Index (PASI) 75 response within 16 weeks of administration ofthe first dose.

Embodiment 44: The method of Embodiment 42 or 43, wherein when themethod is used to treat a population of subjects, a portion of thesubjects in the treated population achieve a PASI 75 response within 16weeks of administration of the first dose. In certain embodiments ofEmbodiment 44, at least 10%, at least 15%, at least 20%, at least 25%,at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population achieve a PASI 75 response within 16weeks of administration of the first dose. In other embodiments ofEmbodiment 44, a statistically significant population of the subjects inthe treated population achieve a PASI 75 response within 16 weeks ofadministration of the first dose.

Embodiment 45: The method of any one of Embodiments 1-44 or 46-77,wherein the subject is an adult subject, or the subjects in the treatedpopulation are adult subjects.

Embodiment 46: The method of any one of Embodiments 1-12, wherein theASAS40 response is maintained or improved after Week 14 by continuing toadminister the daily dose. In one aspect, the ASAS40 response ismaintained or improved up to and including Week 64.

Embodiment 47: The method of any one of Embodiments 1-12, wherein thesubject or subjects in the treated population further achieve ASAS40within 2 weeks of administration of the first dose.

Embodiment 48: The method of any one of Embodiments 1-12, wherein thesubject or subjects in the treated population further achieved ASAS40within 2 weeks of administration of the first dose, and wherein theASAS40 is maintained or improved after Week 14 by continuing toadminister the daily dose.

Embodiment 49: In another aspect, provided is a method of treatingactive ankylosing spondylitis in a subject in need thereof, the methodcomprising orally administering to the subject once a day for at least14 weeks a dose of upadacitinib freebase, or a pharmaceuticallyacceptable salt thereof, in an amount sufficient to deliver 15 mg ofupadacitinib freebase equivalent, wherein the subject achieves ASASpartial remission (PR), ASDAS low disease activity (LDA), ASDAS inactivedisease (ID). ASDAS major improvement (MI), and/or ASDAS clinicallyimportant improvement (CII) within 14 weeks of administration of thefirst dose.

Embodiment 50: The method of Embodiment 49, wherein when the method isused to treat a population of subjects, a portion of the subjects in thetreated population achieve ASAS partial remission (PR). ASDAS lowdisease activity (LDA), ASDAS inactive disease (ID), ASDAS majorimprovement (MI), and/or ASDAS clinically important improvement (CII)within 14 weeks of administration of the first dose. In certainembodiments of Embodiment 50, at least 10%, at least 15%, at least 20%,at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%of the subjects in the treated population achieve ASAS partial remission(PR), ASDAS low disease activity (LDA). ASDAS inactive disease (ID),ASDAS major improvement (MI), and/or ASDAS clinically importantimprovement (CII) within 14 weeks of administration of the first dose.In certain embodiments of Embodiment 50, a statistically significantpopulation of subjects in the treated population achieves ASAS partialremission (PR), ASDAS low disease activity (LDA). ASDAS inactive disease(ID), ASDAS major improvement (MI), and/or ASDAS clinically importantimprovement (CII) within 14 weeks of administration of the first dose.

Embodiment 51: The method of Embodiment 49 or 50, wherein the subject orsubjects in the treated population further achieve within 14 weeks ofadministration of the first dose each result.

Embodiment 52: The method of any one of Embodiments 49-51, wherein thesubject or subjects in the treated population fulfill the 1984 modifiedNew York Criteria for ankylosing spondylitis at baseline.

Embodiment 53: The method of any one of Embodiments 49-51, wherein thesubject or subjects in the treated population fulfill the 2009 ASASclassification criteria at baseline.

Embodiment 54: The method of any one of Embodiments 49-53, wherein thesubject or subjects in the treated population meet at least one criteriaat baseline selected from the group consisting of:

-   -   a. a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)        score≥4;    -   b. an Ankylosing Spondylitis Disease Activity Score (ASDAS) of        ≥2.1; and    -   c. a Patient's Assessment of Total Back Pain (Total Back Pain        score) of ≥4 based on a 0-10 numerical rating scale.

Embodiment 55: The method of any one of Embodiments 49-54, wherein thesubject or subjects in the treated population are biologicdisease-modifying anti-rheumatic drug (bDMARD) naïve at baseline.

Embodiment 56 The method of any one of Embodiments 49-55, wherein thesubject or subjects in the treated population have had an inadequateresponse or intolerance to a biologic disease-modifying anti-rheumaticdrug (bDMARD) at baseline.

Embodiment 57: The method of Embodiments 56, wherein prior toadministration of the first dose, the subject or subjects in thepopulation have been administered one bDMARD, and discontinued use ofthe bDMARD due to intolerance or lack of efficacy.

Embodiment 58: The method of Embodiments 57, wherein the bDMARD is atumor necrosis factor (TNF) inhibitor or an interleukin (IL)-17inhibitor.

Embodiment 59: The method of any one of Embodiments 49-58, wherein thesubject or subjects in the population have had an inadequate response orintolerance to at least two NSAIDs, intolerance to NSAIDS, and/orcontraindication for NSAIDs at baseline.

Embodiment 60: The method of any one of Embodiments 49-59, wherein theASAS partial remission (PR), ASDAS low disease activity (LDA). ASDASinactive disease (ID), ASDAS major improvement (MI), and/or ASDASclinically important improvement (CII) is maintained or improved afterWeek 14 by continuing to administer the daily dose.

Embodiment 61: The method of any one of Embodiments 49-60, wherein thesubject or subjects in the treated population further achieve ASASpartial remission (PR), ASDAS low disease activity (LDA). ASDAS inactivedisease (ID), ASDAS major improvement (MI), and/or ASDAS clinicallyimportant improvement (CII) within 2 weeks of administration of thefirst dose. In certain embodiments of Embodiment 61, a statisticallysignificant population of subjects in the treated population achieveASAS partial remission (PR), ASDAS low disease activity (LDA). ASDASinactive disease (ID), ASDAS major improvement (MI), and/or ASDASclinically important improvement (CII) within 2 weeks of administrationof the first dose. In certain embodiments of Embodiment 61, at least10%, at least 15%, at least 20%, at least 25%, at least 30%, at least35%, at least 40%, or at least 45% of the subjects in the treatedpopulation achieve ASAS partial remission (PR), ASDAS low diseaseactivity (LDA), ASDAS inactive disease (ID). ASDAS major improvement(MI), and/or ASDAS clinically important improvement (CII) within 2 weeksof administration of the frst dose.

Embodiment 62: The method of any one of Embodiments 2341, wherein theACR score is maintained or improved after Week 12 by continuing toadminister the daily dose.

Embodiment 63: The method of any one of Embodiments 2341 or 62, whereinthe subject or subjects in the treated population further achieve ACR20within 2 weeks of administration of the first dose.

Embodiment 64: The method of any one of Embodiments 42-44, wherein thesubject or subjects in the treated population achieve a Psoriasis AreaSeverity Index (PAST) 90 response within 16 weeks of administration ofthe first dose.

Embodiment 65: The method of any one of Embodiments 42-44 or 64, whereinthe PASI response is maintained or improved after Week 16 by continuingto administer the daily dose.

Embodiment 66: In another aspect, provided is a method of treatingactive psoriatic arthritis in a subject in need thereof, the methodcomprising orally administering to the subject once a day for at least24 weeks a dose of upadacitinib freebase, or a pharmaceutically acceptthereof, in an amount sufficient to deliver 15 mg of upadacitinibfreebase equivalent, wherein the subject achieves Minimal DiseaseActivity (MDA) within 24 weeks of administration of the first dose.

Embodiment 67: In another aspect, provided is a method of treatingactive psoriatic arthritis in a subject in need thereof, the methodcomprising orally administering to the subject once a day for at least24 weeks a dose of upadacitinib freebase, or a pharmaceuticallyacceptable salt thereof, in an amount sufficient to deliver 30 mg ofupadacitinib freebase equivalent, wherein the subject achieves MinimalDisease Activity (MDA) within 24 weeks of administration of the firstdose.

Embodiment 68: The method of Embodiment 66 or 67, wherein when themethod is used to treat a population of subjects, a portion of thesubjects in the treated population achieve Minimal Disease Activity(MDA) within 24 weeks of administration of the first dose. In certainembodiments of Embodiment 68, a statistically significant population ofthe subjects in the treated population achieve Minimal Disease Activity(MDA) within 24 weeks of administration of the first dose. In certainembodiments of Embodiment 68, at least 10%, at least 15%, at least 20%,at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%of the subjects in the treated population achieve Minimal DiseaseActivity (MDA) within 24 weeks of administration of the first dose.

Embodiment 69: The method of any one of Embodiments 66-68, wherein thesubject or subjects in the treated population further achieve aPsoriasis Area Severity Index (PAST) response selected from a PAST 75response, a PAST 90 response, and a PAST 100 response, within 16 weeksof administration of the first dose, and the PASI response is maintainedor improved after Week 16 by continuing to administer the daily dose. Incertain embodiments of Embodiment 69, a statistically significantpopulation of subjects in the treated population achieve a PAST 75response, a PASI 90 response, and a PAST 100 response within 16 weeks ofadministration of the first dose. In certain embodiments of Embodiment69, at least 10%, at least 15%, at least 20%, at least 25%, at least30%, at least 35%, at least 40/o, or at least 45% of the subjects in thetreated population achieve a PAST 75 response, a PAST 90 response, and aPASI 100 response within 16 weeks of administration of the first dose.

Embodiment 70: The method of any one of Embodiments 23-42, wherein thesubject or subjects in the treated population achieve a Psoriasis AreaSeverity Index (PAST) 75 response within 16 weeks of administration ofthe first dose. In certain embodiments of Embodiment 70, a statisticallysignificant population of subjects in the treated population achieve aPASI 75 response within 16 weeks of administration of the first dose. Incertain embodiments of Embodiment 70, at least 10%, at least 15%, atleast 20%, at least 25%, at least 30%, at least 35%, at least 40%, or atleast 45% of the subjects in the treated population achieve a PASI 75response within 16 weeks of administration of the first dose.

Embodiment 71: The method of any one of Embodiments 23-42 or 70, whereinthe subject or subjects in the treated population achieve a PsoriasisArea Severity Index (PAST) 90 response within 16 weeks of administrationof the first dose.

Embodiment 72: The method of any one of Embodiments 23-42 or 70-71,wherein the subject or subjects in the treated population achieve aPsoriasis Area Severity Index (PASI) 100 response within 16 weeks ofadministration of the first dose.

Embodiment 73: In another aspect, provided is a method of treatingactive psoriatic arthritis in a subject in need thereof, the methodcomprising orally administering to the subject once a day for at least16 weeks a dose of upadacitinib freebase, or a pharmaceuticallyacceptable salt thereof, in an amount sufficient to deliver 15 mg ofupadacitinib freebase equivalent, wherein the subject achieves aPsoriasis Area Severity Index (PAST) 75 response within 16 weeks ofadministration of the first dose.

Embodiment 74: In another aspect, provided is a method of treatingactive psoriatic arthritis in a subject in need thereof, the methodcomprising orally administering to the subject once a day for at least16 weeks a dose of upadacitinib freebase, or a pharmaceuticallyacceptable salt thereof, in an amount sufficient to deliver 30 mg ofupadacitinib free base equivalent, wherein the subject achieves aPsoriasis Area Severity Index (PASI) 75 response within 16 weeks ofadministration of the first dose.

Embodiment 75: The method of Embodiment 73 or 74, wherein when themethod is used to treat a population of subjects, a portion subjects inthe treated population achieve a PASI 75 response within 16 weeks ofadministration of the first dose. In certain embodiments of Embodiment75, a statistically significant population of subjects in the treatedpopulation achieve a PAST 75 response within 16 weeks of administrationof the first dose. In certain embodiments of Embodiment 75, at least10%, at least 15%, at least 20%, at least 25%, at least 30%, at least35%, at least 40%, or at least 45% of the subjects in the treatedpopulation achieve a PASI 75 response within 16 weeks of administrationof the first dose.

Embodiment 76: The method of any one of Embodiments 73-75, wherein thesubject or subjects in the treated population achieve a Psoriasis AreaSeverity Index (PASI) 90 response within 16 weeks of administration ofthe first dose.

Embodiment 77: The method of any one of Embodiments 73-76, wherein thesubject or subjects in the treated population achieve a Psoriasis AreaSeverity Index (PASI) 100 response within 16 weeks of administration ofthe first dose.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows the ACR20. ACR50, and ACR70 response rate at week 12following administration of placebo or various doses of Compound 1 tosubjects with active rheumatoid arthritis and prior inadequate responseor intolerance to an anti-TNF biologic agent (*P<0.05; **P<0.01;***P<0.001 relative to placebo; modified intent-to-treat population(NRI)). FIG. 1B shows the ACR20 response rate at week 12 in the samepopulation, broken down by number of prior anti-TNF biologic agents.

FIGS. 2A-2D show the ACR20 (FIG. 2A), ACR50 (FIG. 2B), and ACR70 (FIG.2C) responses or DAS28(CRP) mean change from baseline (FIG. 2D) overtime following administration of placebo or various doses of Compound 1to subjects with active rheumatoid arthritis and prior inadequateresponse or intolerance to an anti-TNF biologic agent (*P<0.05;**P<0.01; ***P<0.001 relative to placebo; modified intent-to-treatpopulation (NRI)).

FIG. 2E shows the subjects achieving a DAS28(CRP) score of ≤3.2 or <2.6at week 12 in the same population.

FIG. 2F shows the subjects achieving low disease activity (LDA) orclinical remission (CR) based on clinical disease activity index (CDAI)criteria (LDA is CDAI 510; CR is CDAI≤2.8) at week 12 in the samepopulation.

FIG. 3A shows the mean hemoglobin levels overtime for all subjectsfollowing administration of placebo or various doses of Compound 1 tosubjects with active rheumatoid arthritis and prior inadequate responseor intolerance to an anti-TNF biologic agent (safety population withobserved data (no imputation of missing values)).

FIG. 3B shows the mean hemoglobin change from baseline over time insubjects with high-sensitivity C-reactive protein (hsCRP) greater thanthe upper limit of normal (ULN) (normal ranges for hemoglobin: 11.5-15.5g/dL in females and 13.2-17.0 g/dL in males; ULN for hsCRP=5 mg/L).

FIG. 4 shows the subject disposition for the study described in Example55.

FIGS. 5A and 5B show the subject disposition for the study described inExample 56.

FIG. 6 shows the ACR20. ACR50, and ACR70 responses at week 12 followingadministration of placebo or various doses of Compound 1 to subjectswith active rheumatoid arthritis and inadequate response to methotrexate(*P<0.05; **P<0.01; ***P<0.001 relative to placebo; modifiedintent-to-treat population with NRI of missing values).

FIGS. 7A-7D show the ACR20 (FIG. 7A, NRI analysis), ACR50 (FIG. 7B, NRIanalysis), and ACR70 (FIG. 7C, NRI analysis) responses or DAS28(CRP)mean change from baseline (FIG. 7D, observed cases) over time followingadministration of placebo or various doses of Compound 1 to subjectswith active rheumatoid arthritis and inadequate response to methotrexate(*P<0.05; **P<0.01; ***P<0.001 relative to placebo; modifiedintent-to-treat population).

FIGS. 8A and 8B show subjects achieving a DAS28(CRP) score of ≤3.2 or<2.6 (FIG. 8A) or CDAI of ≤10 or ≤2.8) at week 12 followingadministration of placebo or various doses of Compound 1 to subjectswith active rheumatoid arthritis and inadequate response to methotrexate(*P<0.05; **P<0.01; ***P<0.001 relative to placebo; modifiedintent-to-treat population (NRI)). For FIGS. 8A and 8B, the bottomnumber indicates the percentage of subjects who achieved both cutoffvalues, the middle number indicates the percentage of subjects whoachieved the less stringent cutoff but not the more stringent cutoffvalue, and the top number indicates the percentage of patients whoachieved either cutoff value.

FIGS. 9A-9C show the mean change in hemoglobin from baseline overtime bytreatment group in all subjects (FIG. 9A), subjects with hsCRP≤5 mg/mLat baseline (FIG. 9B), and subjects with hsCRP>5 mg/mL at baseline (FIG.9C) following administration of placebo or various doses of Compound 1to subjects with active rheumatoid arthritis and inadequate response tomethotrexate (safety population with observed data (no imputation ofmissing values)).

FIG. 10 depicts the Phase 2/3 Ankylosing Spondylitis (SELECT-AXIS 1)clinical study plan. Asterisk (*) indicates radiographs were conductedduring the screening period. ASAS40=Assessment of SpondyloArthritisinternational Society 40% response. MRI=magnetic resonance imaging.QD=once daily. SI=sacroiliac.

FIG. 11 depicts the multiplicity-controlled analysis used in the Phase2/3 Ankylosing Spondylitis (SELECT-AXIS 1) clinical trial using theHochberg Procedure. Asterisk (*) indicates result was statisticallysignificant in multiplicity-controlled analysis, otherwise nominal pvalues are shown. The multiplicity-controlled endpoints are tested in asequential manner with initially assigned α=0.05. Statisticalsignificance (p<0.05) can be claimed for a lower ranked endpoint only ifthe previous endpoint in the sequence meets the requirements ofstatistical significance. ASAS HI can be evaluated only if the group ofendpoints tested by Hochberg procedure are all statisticallysignificant. Within the Hochberg procedure. BASDAI50. BASFI, and ASAS PRachieved the required statistical significance; however, WPAI, MASES,BASMI, and ASQoL did not meet the requirement of statisticalsignificance, so ASAS HI was not tested. Per Hochberg procedure, allendpoints are tested using assigned α according to the magnitude ofnominal p value starting from the largest one. If an endpoint isrejected, all endpoints with smaller p values are rejected. If anendpoint fails, then the procedure advances to the next endpoint.ASAS=Assessment of SpondyloArthritis International Society. ASAS40=ASAS40% response. ASAS HI=ASAS Health Index. ASAS PR=ASAS Partial Remission.ASDAS=Ankylosing Spondylitis Disease Activity Score. ASQoL=AnkylosingSpondylitis Quality of Life. BASDAI50=50% improvement from baseline inBath Ankylosing Spondylitis Disease Activity Index. BASFI=BathAnkylosing Spondylitis Functional Index. BASMI=Bath AnkylosingSpondylitis Metrology Index. MASES=Maastricht Ankylosing SpondylitisEnthesitis Score. MRI=magnetic resonance imaging. QD=once daily.SPARCC=Spondyloarthritis Research Consortium of Canada. WPAI=WorkProductivity and Activity Impairment.

FIGS. 12A-12C and FIGS. 12D-12N, respectively depict the Week 14 resultsof the Phase 2/3 Ankylosing Spondylitis (SELECT-AXIS 1) clinical trialfor key clinical efficacy endpoints, and time course of key endpoints upto and including Week 64. FIG. 12A depicts the ASAS20, ASAS40, ASAS PR,and BASDAI50 Responses at Week 14; FIG. 12B depicts the change fromBaseline in SPARCC MRI Spine and SI Joint Scores at Week 14; and FIG.12C depicts other Multiplicity-Controlled Key Secondary EfficacyEndpoints at Week 14. The results demonstrate the study met its primaryendpoint, with statistically significantly more patients treated withupadacitinib freebase versus placebo achieving ASAS40 response at Week14 (48/93 [51.6%] vs 24/94 [25.5%]; p=0.0003) with a treatmentdifference (95% CI) of 26.1% (12.6-39.5%). All endpoints weremultiplicity controlled, except for ASAS20 and SPARCC MRI ST joint. Themultiplicity-controlled secondary endpoints were tested in a sequentialmanner: ASDAS, SPARCC MRI Spine, group of endpoints tested by Hochbergprocedure (BASDAI50, ASQoL, ASAS PR, BASFI, BASMI, MASES, and WPAI), andASAS HI. For FIGS. 12L-12N, Asterisk (***) indicates P<0.001. Asterisk(**) P<0.01; and Asterisk (*) P<0.05. For other Figures. Asterisk (*)indicates statistically significant in multiplicity-controlled analysis,otherwise nominal p values are shown. Accounting for multiplicityadjustment, change from baseline to Week 14 in ASDAS (FIG. 12C), SPARCCMRI spine (FIG. 12B), and BASFI (FIG. 12C) and proportion of patientswho achieved BASDAI50 (FIG. 12A) and ASAS PR (FIG. 12A) werestatistically significant for upadacitinib freebase versus placebo.FIGS. 12D-12K depict the time course of the ASAS40 (FIG. 12D), ASAS20(FIG. 12E), ASAS partial remission (PR) (FIG. 12F), BASDA150 Responses(FIG. 12G), ASDAS inactive disease (ID) (FIG. 12H), ASDAS low diseaseactivity (LDA) (FIG. 12I), ASDAS major improvement (MI) (FIG. 12J), andASDAS clinically important improvement (CII) (FIG. 12K) up to andincluding Week 64. At week 14, the placebo group was rescued andadministered 15 mg upadacitinib free base (Placebo→Upadacitinib 15 mgQD). Patients who switched from placebo to upadacitinib at week 14showed a similar efficacy response compared with those who receivedcontinuous upadacitinib free base from Day 0. The data suggestsupadacitinib 15 mg QD, showing achievement of efficacy at Week 14, andsustaining or even improving upon this efficacy up to and including Week64, will help to address an unmet need for patients with AS (as well asin patients with non-radiographic axial spondyloarthritis (nr-axSpA)),especially in those patients who have active disease and haveinadequately responded to NSAIDs. A significantly higher proportion ofpatients receiving upadacitinib versus placebo achieved≥30/6 (FIG. 12L)and ≥50% reduction (FIG. 12M) in Patient's Global Assessment of pain(PtPain) as early as week 2, and ≥70% reduction (FIG. 12N) as early asweek 4, and efficacy achieved was sustained thereafter. Patients whoswitched from placebo to open-label upadacitinib at week 14 generallyreached the same level of pain reduction after week 14 as thoseinitially randomized to upadacitinib. MASES assessment includes patientswith baseline enthesitis; WPAI assessment includes patients currentlyemployed; SPARCC MRI assessment population as pre-specified in thestatistical analysis plan (baseline included MRI data 3 days after firstdose of study drug, and Week 14 included MRI data up to first dose ofPeriod 2 study drug). ASAS20=Assessment of SpondyloArthritisinternational Society 20 response. ASAS40=Assessment ofSpondyloArthritis international Society 40 response. ASQoL=AnkylosingSpondylitis Quality of Life score. ASDAS=Ankylosing Spondylitis DiseaseActivity Score. BASDAI50=50% improvement from baseline in BathAnkylosing Spondylitis Disease Activity Index. BASFI=Bath AnkylosingSpondylitis Functional Index. BASMI=Bath Ankylosing SpondylitisMetrology Index. HI=Health Index. MASES=Maastricht AnkylosingSpondylitis Enthesitis Score. MRI=magnetic resonance imaging. MMRM=mixedmodel for repeated measures. NRI=non-responder imputation. AO=AsObserved. PR=partial remission. QD=once daily. SI, sacroiliac.SPARCC=Spondyloarthritis Research Consortium of Canada. WPAI=WorkProductivity and Activity Impairment.

FIGS. 13A-13E depict data for ASAS domains (ASAS40, PtGA, Back Pain,BASFI, and Inflammation) measured at Weeks 2, 4, 8, 12, and 14 in thePhase 2/3 Ankylosing Spondylitis (SELECT-AXIS 1) clinical trial. Asignificant difference for upadacitinib freebase versus placebo inASAS40 (FIG. 13A) and the mean change for each of its four individualdomains (FIGS. 13B-13E) was observed as early as the first post-baselinevisit (Week 2), and this difference was maintained consistently throughWeek 14, with Week 14 achieving a statistically significant differencein multiplicity-controlled analysis. Back pain defined on a numericalrating scale (0-10) based on the following question, “What is the amountof back pain that you experienced at any time during the last week?Inflammation is defined as mean of Questions 5 and 6 of the BASDAI.BASDAI=Bath Ankylosing Spondylitis Disease Activity Index. BASFI=BathAnkylosing Spondylitis Functional Index. BL=baseline. LSM=least squaresmean. MMRM=mixed model for repeated measures. NRI=non-responderimputation. PtGA=Patient Global Assessment of disease activity. QD=oncedaily.

FIG. 14 depicts the pre-specified and supplemental SPARCC MRI Analysisof the Phase 2/3 Ankylosing Spondylitis (SELECT-AXIS 1) clinical trial.The SPARCC MRI assessment population was pre-specified in thestatistical analysis plan (baseline included MRI data ≤3 days afterfirst dose of study drug, and Week 14 included MRI data up to first doseof period 2 study drug). The supplemental SPARCC MRI analysis includedall MRI data collected at nominal visits at baseline and Week 14, andconfirmed the results of the primary SPARCC MRI analysis for both thespine and SI joints. MMRM=mixed model for repeated measures.MRI=magnetic resonance imaging. QD=once daily. SI=sacroiliac.SPARCC=Spondyloarthritis Research Consortium of Canada.

FIGS. 15A-15D depict the cumulative probability plots of change inSPARCC scores as described in FIG. 14 for the Phase 2/3 AnkylosingSpondylitis (SELECT-AXIS 1), demonstrating that the SPARCC MRI spine andSI joint scores improved from baseline to week 14 to a greater extent inpatients receiving upadacitinib compared with placebo. Results for theprimary MRI analyses (FIGS. 15A-15B) and supplemental MRI analyses(FIGS. 15C-15D) were consistent.

FIGS. 16A-16C depict the percentage of patients achieving ASDAS LDA,ASDAS ID, ASDAS CII, and ASDAS MI at Week 14 (FIG. 16A), Change FromBaseline in Mean ASDAS Over Time (FIG. 16B), and ASDAS MI Over Time(FIG. 16C) in the Phase 2/3 Ankylosing Spondylitis (SELECT-AXIS 1)clinical trial. The proportions of patients who achieved ASDAS LDA,ASDAS ID. ASDAS CII, and ASDAS MI were greater (nominal p<0.0001) forupadacitinib freebase versus placebo at Week 14 (FIG. 16A).ASDAS=Ankylosing Spondylitis Disease Activity Score. BL=baseline.CII=Clinically Important Improvement (≥1·1-point decrease frombaseline). ID=Inactive Disease (score<1·3). LDA=low disease activity(<2.1). MI=Major Improvement (≥2-point decrease from baseline).MMRM=mixed model for repeated measures. NRI=non-responder imputation.QD=once daily.

FIGS. 17A-17D depict the least squares mean (LSM) change from baselinein individual ASDAS components over time in the Phase 2/3 AnkylosingSpondylitis (SELECT-AXIS 1) clinical trial. Improvement in the meanASDAS (FIG. 16B) and the individual ASDAS components (FIGS. 17A-17D) wasseen as early as Week 2 with continued improvement up to Week 14 withupadacitinib freebase. Spinal pain=BASDAI Question 2. Peripheralpain/swelling=BASDAI Question 3. Duration of morning stiffness=BASDAIQuestion 6. ASDAS=Ankylosing Spondylitis Disease Activity Score.BASDAI=Bath Ankylosing Spondylitis Disease Activity Index. BL=baseline,hsCRP=high-sensitivity C-reactive protein. MMRM=mixed model for repeatedmeasures. PtGA=Patient Global Assessment of disease activity. QD=oncedaily.

FIG. 18 depicts the Phase 3 Study design for SELECT-PSA1 in subjectswith active PsA and a previous inadequate response to at least onenon-biologic DMARD (PsA DMARD-IR). a. All subjects will receive x-raysof hands and feet at Screening, Week 24, Week 56, Week 104, and Week152. b. At Week 16 rescue therapy will be offered to subjects classifiedas non-responders (defined as not achieving at least 20% improvement ineither or both tender joint count (TJC) and swollen joint count (SJC) atboth Week 12 and Week 16). c. At Week 24, all placebo subjects willswitch to upadacitinib freebase 15 mg QD or 30 mg QD (1:1 ratio)regardless of response.

FIGS. 19A-19B depict the graphical testing procedure in the Phase 3SELECT-PSA1 (PsA DMARD-IR) for the primary endpoint (ACR20 response atWeek 12) and ranked secondary endpoints. The overall type I error ratewas controlled at the 2-sided 0.05 level (including a 0.0001 α for theinterim futility analysis). FIG. 19A, Part 1, describes the testingsequence of the adequately powered ranked secondary endpoints in PsAsymptoms and radiographic progression. FIG. 19B, Part 2, describes thetesting sequence of additional ranked secondary endpoints includingsuperiority tests versus adalimumab. Part 2 endpoints are tested onlyafter statistical significance of all Part 1 endpoints are achieved.

FIGS. 20A-20EE provide a summary of primary and key secondary efficacyresults for the SELECT-PSA1 (PsA DMARD-IR) Phase 3 clinical trial. FIG.20A depicts the time course of the ACR20 response and associated 95%confidence interval (CI) up to and including Week 24. Response rate (%)with 95% CI is presented by visit. Nominal p-value<0.05 for both UPAdoses vs placebo for all visits. UPA=upadacitinib freebase;ADA=adalimumab; QD=once daily; EOW=every other week. Symbols: ***,P<0.001 for upadacitinib vs. placebo; ###, P<0.001 for upadacitinib vs.adalimumab; ζζζ. P<0.001 for non-inferiority upadacitinib vs.adalimumab. Additional key secondary efficacy results include: patientsachieving ACR50 response (FIG. 20B); patients achieving ACR70 response(FIG. 20C); patients achieving Minimal Disease Activity (MDA) (FIG.20D); patients achieving Non-inferiority of Upadacitinib versusAdalimumab in ACR20 at Week 12 (FIG. 20E); patients achieving LS meanchange from baseline over 24 weeks in core components of the ACRcriteria: tender joint count (TJC68) (FIG. 20F), swollen joint count(SJC66) (FIG. 20G), Physician's global assessment of disease activity(PhGA) (FIG. 20H), patient's global assessment of disease activity(PtGA) (FIG. 20I), Pain (PtPain) (score of 0 indicates “no pain” and ascore of 10 indicates “worst possible pain”) (FIG. 20J), andhigh-sensitivity C-reactive protein (hs-CRP) (FIG. 20K); proportion ofpatients achieving Psoriasis Area Severity Index PASI 75 (FIG. 20L),PASI 9) (FIG. 20M), and PASI 100 (FIG. 20N) over 24 weeks, wherein afterweek 16 assessments were performed and patients were able to useconcomitant treatments specifically for psoriasis per investigatorjudgment; proportions of patients achieving Static Investigator GlobalAssessment (sIGA) over 24 weeks (FIG. 20O); change from baseline over 24weeks in Self-Assessment of Psoriasis Symptoms (SAPS) (FIG. 20P);patients achieving change from baseline over 24 weeks in healthassessment questionnaire disability index (HAQ-DI) (FIG. 20Q) and SF-36Physical Component Summary Score (the PCS is one of two summary scorescalculated from the eight SF-36 domains. A linear algorithm is appliedto calculate the PCS which has normative mean value of 50, with higherscores indicating better outcomes) (FIG. 20R); patients achieving changefrom baseline over 24 weeks in Functional Assessment of Chronic IllnessTherapy-Fatigue (FACIT-F) (the FACIT-F score ranges from 0-52, withhigher scores indicating less fatigue) (FIG. 20S); patients achievingchange from baseline over 24 weeks in Morning Stiffness (Mean of BASDAIQuestions 5 and 6) (FIG. 20T), Morning Stiffness Severity (BASDAIQuestion 5) (FIG. 20U), and Morning Stiffness Duration (BASDAI Question6) (FIG. 20V); Proportion of Patients with Resolution of Enthesis Over24 Weeks by Leeds Enthesitis Indices (LEI) (FIG. 20W), bySpondyloarthritis Research Consortium of Canada (SPARCC) (FIG. 20X), andProportion of Patients with Resolution of Dactylitis by Leeds DactylitisIndex (LDI) (FIG. 20Y); patients achieving change from baseline at Week24 in radiographic endpoints (mTSS=modified total Sharp/van der HeijdeScore. JSN=joint space narrowing score) (FIG. 20Z); and proportion ofpatients with no radiographic progression mTSS≤0.0 ((FIG. 20AA) andmTSS≤0.5 at Week 24 (FIG. 20BB). A significantly higher proportion ofpatients receiving upadacitinib freebase (15 mg QD or 30 mg QD) versusplacebo achieved≥30% and ≥50% reduction in Patient's Global Assessmentof pain (PtPain) as early as week 2, and efficacy achieved was sustainedthereafter (see FIGS. 20CC and 20DD). A significantly higher proportionof patients receiving upadacitinib freebase versus placebo achieved≥70/oreduction in PtPain as early as week 2 (30 mg QD upadacitinib) or asearly as week 4 (15 mg QD upadacitinib), and efficacy achieved wassustained thereafter (see FIG. 20EE). Symbols: *, statisticallysignificant at 0.05 level (UPA 15 mg QD); ζ statistically significant at0.05 level (UPA 30 mg QD); #, statistically significant at 0.05 level(ADA 40 mg EOW);***, P<0.001 for upadacitinib vs. placebo; ###, P<0.001for upadacitinib vs. adalimumab; ζζζ P<0.001 for non-inferiorityupadacitinib vs. adalimumab; PBO=placebo; ADA=adalimumab;UPA=upadacitinib freebase; EOW=every other week; QD=once daily;CI=confidence interval.

FIG. 21 depicts the Phase 3 Study design for SELECT-PSA2 in subjectswith active PsA and a previous inadequate response to at least onebDMARD (PsA bDMARD-IR). a. At Week 16 rescue therapy will be offered tosubjects classified as non-responders (defined as not achieving at least20% improvement in either or both tender joint count (TJC) and swollenjoint count (SJC) at both Week 12 and Week 16). b. At Week 24, allplacebo subjects will switch to upadacitinib freebase 15 mg QD or 30 mgQD (1:1 ratio) regardless of response.

FIGS. 22A-22DD provides a summary of primary and key secondary efficacyresults for the SELECT-PSA2 (PsA bDMARD-IR) Phase 3 clinical trial. FIG.22A depicts the time course up to and including Week 24 of the primaryendpoint ACR20. Response rate (%) with 95% CI is presented by visit.Nominal p-value<0.05 for both UPA doses vs placebo for all visits.UPA=upadacitinib freebase. Symbols: * =p≤0.05 for comparison ofupadacitinib 15 mg QD versus placebo; #=p≤0.05 for comparison ofupadacitinib 30 mg QD versus placebo; †=significant in themultiplicity-controlled analysis. Additional key secondary efficacyresults include: patients achieving ACR50 response (FIG. 22B); patientsachieving ACR70 response (FIG. 22C); proportion of patients achievingMinimal Disease Activity (MDA) over 24 weeks (FIG. 22D); patientsachieving change in baseline in Leeds Enthesitis Index (LEI) (FIG. 22E);patients achieving resolution of enthesitis (LEI=0) (FIG. 22F);proportion of patients with resolution of enthesitis over 24 weeks bySpondyloarthritis Research Consortium of Canada (SPARCC) (FIG. 22G);patients achieving change in baseline in Leeds Dactylitis Index (LDI)(FIG. 22H); patients achieving resolution of dactylitis (LDI=0) (FIG.221); proportion of patients achieving Psoriasis Area Severity IndexPAST 75 (FIG. 22J), PAST 90 (FIG. 22K), and PAST 100 Response (FIG. 22L)over 24 weeks; patients achieving change from baseline in diseaseactivity in psoriatic arthritis (DAPSA) score (FIG. 22M); patientsachieving change from baseline over 24 weeks in core components of theACR criteria; tender joint count (TJC68) (FIG. 22N), swollen joint count(SJC66) (FIG. 22O), physician's global assessment of disease activity(PhGA) (FIG. 22P), patient's global assessment of disease activity(PtGA) (FIG. 22Q), Pain (PtPain) (a score of 0 indicates “no pain” and ascore of 10 indicates “worst possible pain”) (FIG. 22R),high-sensitivity C-reactive protein (hs-CRP) (FIG. 22S); proportions ofpatients achieving static investigator global assessment (sIGA) 0/l over24 weeks (FIG. 22T); patients achieving change from baseline over 24weeks in self-assessment of psoriasis symptoms (SAPS) (FIG. 22U);patients achieving change from baseline over 24 weeks in healthassessment questionnaire disability index (HAQ-DI) (FIG. 22V); patientsachieving change from baseline over 24 weeks in SF-36 Physical ComponentSummary (FIG. 22W); patients achieving change from baseline over 24weeks in Functional Assessment of Chronic Illness Therapy-Fatigue(FACIT-F) (the FACIT-F score ranges from 0-52, with higher scoresindicating less fatigue) (FIG. 22X); patients achieving change frombaseline over 24 weeks in morning stiffness (mean of BASDAI Questions 5and 6) (FIG. 22Y); patients achieving change from baseline over 24 weeksin morning stiffness severity (BASDAI Question 5) (FIG. 22Z); andpatients achieving change from baseline over 24 weeks in morningstiffness duration (BASDAI Question 6) (FIG. 22AA). A significantlyhigher proportion of patients receiving upadacitinib freebase (15 mg QDor 30 mg QD) versus placebo achieved≥30%, ≥50%, and ≥70% reduction inPatient's Global Assessment of pain (PtPain) as early as week 2, andefficacy achieved was sustained thereafter (see FIGS. 22BB-22DD).UPA=upadacitinib; PBO=placebo; QD=once daily; NRI=non-responderimputation.

FIG. 23 depicts the Phase 3 study design for the treatment of AS andnr-AxSpA subjects. AS=ankylosing spondylitis; ASAS=Assessment ofSpondylo Arthritis International Society; bDMARD-IR=biologicdisease-modifying anti-rheumatic drug inadequate responder; EMA=EuropeanMedicines Agency; FDA=Food and Drug Administration; MRI=magneticresonance imaging; nr-axSpA=non-radiographic axial spondyloarthritis;QD=once daily; SI=sacroiliac; UPA=upadacitinib freebase.

DETAILED DESCRIPTION OF THE INVENTION

This written description uses examples to disclose the invention andalso to enable any person skilled in the art to practice the invention,including making and using any of the disclosed solid state forms orcompositions, and performing any of the disclosed methods or processes.The patentable scope of the invention is defined by the claims, and mayinclude other examples that occur to those skilled in the art. Suchother examples are intended to be within the scope of the claims if theyhave elements that do not differ from the literal language of theclaims, or if they include equivalent elements.

I. Definitions

Section headings as used in this section and the entire disclosure arenot intended to be limiting.

Where a numeric range is recited, each intervening number within therange is explicitly contemplated with the same degree of precision. Forexample, for the range 6 to 9, the numbers 7 and 8 are contemplated inaddition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitlycontemplated. In the same manner, all recited ratios also include allsub-ratios falling within the broader ratio.

The singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise.

The term “about” generally refers to a range of numbers that one ofskill in the art would consider equivalent to the recited value (i.e.,having the same function or result). In many instances, the term “about”may include numbers that are rounded to the nearest significant figure.

Unless the context requires otherwise, the terms “comprise,”“comprises,” and “comprising” are used on the basis and clearunderstanding that they are to be interpreted inclusively, rather thanexclusively, and that Applicant intends each of those words to be sointerpreted in construing this patent, including the claims below.

The term “subject” refers to a human subject.

The terms “treating” and “treatment” refer to ameliorating, suppressing,eradicating, reducing the severity of, decreasing the frequency ofincidence of, preventing, reducing the risk of, slowing the progressionof damage caused by or delaying the onset of the condition or improvingthe quality of life of a patient suffering from the condition.

The abbreviation “% CV” refers to the coefficient of variation,expressed as a percent. % CV is calculated according to the followingequation: % CV=(SD/x)*10, wherein x is the mean value and SD is thestandard deviation.

As used herein, the term “entry into a use environment” means contact ofa formulation of the disclosure with the gastric fluids of the subjectto whom it is administered, or with a fluid intended to simulate gastricfluid.

The abbreviation “MTX” refers to methotrexate.

Clinical Endpoint Definitions American College of Rheumatology (ACR)Criteria

ACR criteria is a composite measurement calculated based on theimprovement over a set of core measurements. ACR20 is defined as atleast 20% improvement (compared to baseline values) in tender andswollen joint counts (TJC and SJC) and at least 20% improvement in 3 ofthe remaining 5 core set measures (subject assessment of pain, subjectglobal assessment of disease activity, physician global assessment ofdisease activity, subject assessment of physical function and acutephase reactant hsCRP). ACR50 and ACR70 are similarly defined with atleast 50% and 70% improvement, respectively. A subject will beclassified as an ACR20 (ACR50, or ACR70) responder, if the followingconditions are met:

-   -   1. ≥20% (50%, or 70%) improvement from baseline in tender joint        count (TJC68) and    -   2. ≥20% (50%, or 70%) improvement from baseline in swollen joint        count (SJC66) and    -   3. ≥20% (50%, or 70%) improvement from baseline in at least 3 of        the following 5:        -   a. Patient's Global Assessment of Pain (Pt Pain)        -   b. Patient's Global Assessment of Disease Activity (PtGA)        -   c. Physician's Global Assessment of Disease Activity (PGA)        -   d. Patient's self-assessment of physical function (i.e.,            measured by Health Assessment Questionnaire HAQ-DI score)        -   e. Acute-phase reactant value high-sensitivity CRP (hsCRP)

Assessment of SpondyloArthritis International Society (ASAS). ASAS20,ASAS40, ASAS-PR, and ASAS 5/6 Responses.

Domains used for the ASAS responses are as follows:

-   -   a. Patient's Global Assessment—Represented by the PtGA-disease        activity (NRS score 0-10)    -   b. Pain—Represented by the Patient's Assessment of Total Back        Pain (Total Back Pain, NRS score 0-10)    -   c. Function—Represented by the BASFI (NRS score 0-10)    -   d. Inflammation—Represented by the mean of the 2 morning        stiffness-related BASDAI (mean of Questions 5 and 6 of the        BASDAI NRS score 0-10)

ASAS20 Response: Improvement of ≥20% and absolute improvement of ≥1 unit(on a scale of 0 to 10; 0=no pain and 10=worst possible pain) fromBaseline in ≥3 of the above 4 domains above, with no deterioration(defined as a worsening of ≥20% and a net worsening of ≥1 unit) in thepotential remaining domain.

ASAS40 Response: Improvement of ≥40% and absolute improvement of ≥2units (on a scale of 0 to 10; 0=no pain and 10=worst possible pain) fromBaseline in ≥3 of the above 4 domains above, with no deterioration(defined as a net worsening of >0 units) in the potential remainingdomain.

ASAS partial remission (PR): an absolute score of <2 units (on a scaleof 0 to 10; 0=no pain and 10=worst possible pain) from Baseline for eachof the 4 domains above.

ASAS 5/6 Response: Improvement of ≥20% from Baseline in 5 out of thefollowing 6 domains: BASFI, Patient's Assessment of Total Back Pain,PtGA-disease activity, inflammation (mean of Questions 5 and 6 of theBASDAI]), lateral lumbar flexion from BASMI, and hs-CRP.

ASAS Health Index (HI)

The ASAS HI is a linear composite measure with a dichotomous responseoption: “I agree” and “I do not agree” to a listing of 17 Questions.Each statement on the ASAS HI is given a score of “1”=“I agree” or“0”=“I do not agree.” The total sum of the ASAS HI ranges from 0-17,with a lower score indicating a better health status. Questions 7 and 8are not applicable to all patients. For those patients who ticked theresponse “not applicable,” the sum score is analyzed based on n=16 orn=15 respectively. A total score can be analyzed if no more than 20% ofthe data (i.e., 3 Questions) are missing. The total score is calculatedas follows for respondents with up to a maximum of three missingresponses: Sum.score=x/(17−m)*17, where x is the Question summationscore and m is the number of missing Questions and m≤3. Cases with morethan three missing responses (m>3) cannot be allocated a total score andthe total score will be set as missing. The 17 ASAS Health IndexQuestions are as follows:

-   -   1. Pain sometimes disrupts my normal activities.    -   2. I find it hard to stand for long.    -   3. I have problems running.    -   4. I have problems using toilet facilities.    -   5. I am often exhausted.    -   6. I am less motivated to do anything that requires physical        effort.    -   7. I have lost interest in sex.    -   8. I have difficulty operating the pedals in my car.    -   9. I am finding it hard to make contact with people.    -   10. I am not able to walk outdoors on flat ground.    -   11. I find it hard to concentrate.    -   12. I am restricted in traveling because of my mobility.    -   13. I often get frustrated.    -   14. I find it difficult to wash my hair.    -   15. I have experienced financial changes because of my rheumatic        disease.    -   16. I sleep badly at night.    -   17. I cannot overcome my difficulties.

Ankylosing Spondylitis Disease Activity Score (ASDAS)

Parameters used for the calculation of ASDAS:

-   -   1. Patient's Assessment of Total Back Pain (BASDAI Question 2        NRS score 0-10),    -   2. Duration of morning stiffness (BASDAI Question 6 NRS score        0-10),    -   3. Patient global assessment of disease activity (PtGA NRS score        0-10),    -   4. Peripheral pain/swelling (BASDAI Question 3 NRS score 0-10),        and    -   5. high-sensitivity C reactive protein (hsCRP) (in mg/mL) or        erythrocyte sedimentation rate (ESR).

Calculation of ASDAS:

ASDAS_(hs-CRP) 0.121×total backpain+0.110×PtGA+0.073×peripheral=pain/swelling+0.058×duration of morningstiffness+0.579×Ln(hs-CRP+1).

ASDAS_(ESR)=0.113×patient global+0.293×√ESR+0.086×peripheralpain/swelling+0.069×duration of morning stiffness+0.079×total back pain.

To calculate observed ASDAS scores, the observed component value will becalculated first. Then the components will be included in thecalculation per the ASDAS formula. If any observed component is missingin a window, then the observed ASDAS score will be missing.

When the conventional CRP is below the limit of detection or when thehigh sensitivity CRP is <2 mg/L, the constant value of 2 mg/L should beused to calculate ASDAS-CRP.

ASDAS score is categorized by the following ASDAS Disease ActivityStates:

-   -   ASDAS Inactive Disease (ID): ASDAS<1.3    -   ASDAS Moderate Disease: 1.3≤ASDAS<2.1    -   ASDAS Low Disease Activity (LDA): ASDAS<2.1    -   ASDAS High Disease: 2.1≤ASDAS≤3.5    -   ASDAS Very High Disease: ASDAS>3.5

ASDAS Response categories are defined as follows:

-   -   ASDAS Major Improvement (MI) (a change from baseline≤−2.0:        ≥2-point decrease from baseline)    -   ASDAS Clinically Important Improvement (CII) (a change from        baseline≤−1.1; (≥1.1-point decrease from baseline)

Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL)

Each of the 18 statements on the ASQoL (provided below) is given a scoreof “1” (yes) or “0” (no). Concepts measured include activities of dailylife, emotional functioning, pain, fatigue, and sleep problems. A scoreof “1” is given where the Question is affirmed (with a “yes” answer),indicating adverse QoL. All Question scores are summed to give a totalscore or index. Scores can range from 0 (good QoL) to 18 (poor QoL),with higher scores equaling worsening functioning. Cases with more thanthree missing responses (i.e., more than 20%) cannot be allocated atotal score. For cases with between one and three missing responses, thetotal score is calculated as follows: T=18x/18−m where: T is the totalscore, x is the total score for the Questions affirmed and m is thenumber of missing Questions.

-   -   1. My condition limits the places I can go    -   2. I sometimes feel like crying    -   3. I have difficulty dressing    -   4. I struggle to do jobs around the house    -   5. It's impossible to sleep    -   6. I am unable to join in activities with my friends/family    -   7. I am tired all the time    -   8. I have to keep stopping what I am doing to rest    -   9. I have unbearable pain    -   10. It takes a long time to get going in the morning    -   11. I am unable to do jobs around the house    -   12. I get tired easily    -   13. I often get frustrated    -   14. The pain is always there    -   15. I feel I miss out on a lot    -   16. I find it difficult to wash my hair    -   17. My condition gets me down    -   18. I worry about letting people down

Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASDAI 50Response, and the Morning Stiffness Score

The BASDAI consists of a 1 through 10 scale (1 being no problem and 10being the worst problem) and is used to answer 6 questions pertaining tothe 5 symptoms: Fatigue, Spinal pain, Joint pain/swelling, Areas oflocalized tenderness (also called enthesitis, or inflammation of tendonsand ligaments), Morning stiffness duration, and Morning stiffnessseverity. A lower score indicates less disease activity.

The six BASDAI Questions (Components) are as follows:

-   -   Q1. How would you describe the overall level of        fatigue/tiredness you have experienced?    -   Q2. How would you describe the overall level of AS neck, back or        hip pain you have had?    -   Q3. How would you describe the overall level of pain/swelling in        joints, other than neck, back or hips you have had?    -   Q4. How would you describe the overall level of discomfort you        have had from any areas tender to touch or pressure?    -   Q5. How would you describe the overall level of morning        stiffness you have had from the time you wake up?    -   Q6. How long does your morning stiffness last from the time you        wake up?

Questions 1 through 5 have responses that can range from 0 (none) to 10(very severe); Question 6 have response range from 0 (0 hr) to 10 (2 ormore hrs), with 5 representing 1 hr.

Scoring of the BASDAI: BASDAI will be reported 0 to 10. The score has amaximum value of 10 and is calculated as follows:

BASDAI Score=0.2(Q1+Q2+Q3+Q4+Q5/2+Q6/2)

If one of the 5 Questions (Questions 1-Question 4, inflammation) ismissing, then the score is the mean of the 4 non-missing Questions(total of 4 non-missing Questions divided by 4). If more than 1 of the 5Questions is missing, then the BASDAI score is missing. Question 5 andQuestion 6 jointly constitute Question 5 (inflammation). If bothQuestions 5 and 6 are missing, and questions 1 through 4 arenon-missing, then only one Question will be considered missing. TheBASDAI score can still be calculated as the mean of Questions 1-4.However, if, for example, both Question 6 and Question 1 are missing,then 2 Questions will be considered missing, as the inflammationcalculation would be incomplete. The BASDAI score would then beconsidered missing in this case.

A BASDAI 50 response is a categorical response based on BASDAI thatrepresents an at least 50% improvement from baseline in BASDAI.

The Morning Stiffness Score is the average of BASDAI Questions 5 and 6,and it ranges from 0-10.

A “change from baseline in BASDAI and BASDAI Questions (Components),including change from baseline in mean of Question 5 and 6 of theBASDAI” means (1) a change from baseline from the BASDAI Score, (2) achange from baseline in all of the BASDAI Questions, and (3) a changefrom baseline of the mean of Questions 5 and 6 (which representinflammation).

Bath Ankylosing Spondylitis Functional Index (BASFI)

The BASFI consists of the following 10 questions, assessing ability toperform activities such as dressing, bending, reaching, turning, andclimbing steps, each with a response ranging from 0 (easy) to 10(impossible):

-   -   1. Putting on your socks or tights without help or aids (e.g.,        sock-aid).    -   2. Bending forward from the waist to pick up a pen from the        floor without an aid.    -   3. Reaching up to a high shelf without help or aids (e.g.,        helping hand).    -   4. Getting up out of an armless dining room chair without using        your hands or any other help.    -   5. Getting up off the floor without help from lying on your        back.    -   6. Standing unsupported for 10 minutes without discomfort.    -   7. Climbing 12 to 15 steps without using a handrail or walking        aid. One foot on each step.    -   8. Looking over your shoulder without turning your body.    -   9. Doing physically demanding activities (e.g., physiotherapy,        exercises, gardening, or sports).    -   10. Doing a full day's activities whether at home or at work.

See, e.g., Sieper et al., Ann Rheum Dis (2009) 68 (Suppl II): ii1-ii44.doi:10.1136/ard.2008.104018.

Scoring of BASFI. The BASFI score will be derived based on the averageof Questions 1 through 10. If up to 2 Questions are missing,corresponding scores will be replaced with the mean of the remainingnon-missing Questions. If 3 or more Questions are missing, BASFI will beconsidered missing.

Bath Ankylosing Spondylitis Metrology Linear Index (BASMI_(lin))

The Linear BASMI (BASMI_(lin)) composite score will be calculated usingthe BASMI components. The table below presents the components ofBASM_(lin), and assessment ranges for score.

TABLE 1 Components of BASMI_(lin) 0 Between 0 and 10 10 Lateral Lumbarflexion (cm) A ≥ 21.1 (21.1 − A)/2.1 A ≤ 0.1 Tragus to wall distance(cm) A ≤ 8 (A − 8)/3 A ≥ 38 Lumbar flexion A ≥ 7.4  (7.4 − A)/0.7 A ≤0.4 (modified Schober) (cm) Intermalleolar distance (cm) A ≥ 124.5(124.5 − A)/10   A ≤ 24.5 Cervical rotation (°) A ≥ 89.3 (89.3 − A)/8.5A ≤ 4.3

-   -   BASMI_(lin)=Assessment measurements for tragus to wall, cervical        rotation and lateral lumbar flexion are the means of the left        and right measurement; A=assessment measurement

Scores for each assessment range from 0 to 10, and the BASMI_(lin) totalscore will be the average of the 5 assessment scores. If 1 Question ismissing, the BASMI_(lin) will be calculated as the mean of remaining 4Questions. Hence, the range of the BASMI_(lin) total score should bebetween 0 and 10. If 2 or more Questions are missing, then theBASMI_(lin) score will be considered missing. See e.g., van der Heijdeet al., Arth. Care & Res. (2012) 64:1919-1922 and van der Heijde et al.,Ann Rheum Dis (2008) 67:489-93.

Body Surface Area—Psoriasis (BSA-PS)

The subject's right or left hand should be selected as the measuringdevice. For purposes of clinical estimation, the total surface of thepalm plus five digits will be assumed to be approximately equivalent to1%. Measurement of the total area of involvement is aided by imaginingif scattered plaques were moved so that they were next to each other andthen estimating the total area involved. See, e.g., See, e.g., Bozek andReich, Adv. Clin. Exp. Med. (2017) 26:851-856.

Disease Activity in Psoriatic Arthritis (DAPSA) Score

DAPSA is a continuous endpoint that measures the disease activity inpsoriatic arthritis. DAPSA consists of five components: Tender JointCount 68, Swollen Joint Count 66, Patient's Global Assessment of Pain(Pt Pain) (0-10 NRS), PtGA of Disease Activity (0-10 NRS), and hsCRP (inmg/dL). Calculation of the DAPSA score is as follows:

DAPSA=SJC66+TJC68+Pt Pain(0-10 NRS)+PtGA(0-10 NRS)+hsCRP (in mg/dL)

To calculate observed DAPSA scores, the observed component value will becalculated first. Then the components will be included in thecalculation per the DAPSA formula. If any observed component is missingin a window, then the observed DAPSA score will be missing.

Disease Activity Score (DAS28)

DAS28 (CRP) and DAS28 (ESR) are composite indices to assess diseaseactivity in PsA using high-sensitivity c-reactive protein lab value(hsCRP) or erythrocyte sedimentation rate (ESR) measurement,respectively. The DAS28 provides a score between 0 and 10, indicatingarthritis disease activity at the time of measurement. DAS28 (CRP) andDAS28 (ESR) are calculated based on Tender Joint Count, Swollen JointCount, PtGA of Disease Activity (0-100), and hsCRP (in mg/L) or ESR(mm/hr). As PtGA of Disease Activity is collected with the scale of 0-10NRS, the variable needs to be multiplied by 10 before being used theDAS28 formula. To calculate observed DAS28 scores, the observedcomponent value will be calculated first. Then the components will beincluded in the calculation per the DAS formula selected. If anyobserved component is missing in a window, then the observed DAS28 scorewill be missing. Calculation of DAS28 (CRP) and DAS28 (ESR) are providedby the following equations:

DAS28(CRP)=0.56×√(TJC28)+0.28×√(SJC28)+0.36×ln(hsCRP+1)+0.014×PtGA+0.96

DAS28(ESR)=0.56×√(TJC28)+0.28×√(SJC28)+0.70×ln(ESR)+0.014×PtGA

where is √ square root and ln is natural log; TJC28 refers to theSubject's total Tender Joint Count out of the provided 28 evaluatedjoints; SJC28 refers to the Subject's total Swollen Joint Count out ofthe provided 28 evaluated joints; hsCRP unit in the DAS28 (CRP) equationis expressed as mg/L; ESR unit in the DAS28 (ESR) equation is expressedas mm/hr; and PtGA refers to the Patient's Global Assessment of DiseaseActivity.

TABLE 2 Anatomical Joints for DAS28 (CRP) Calculation Shoulder ElbowWrist Thumb Interphalangeal Metacarpo- Metacarpo- Metacarpo- Metacarpo-phalangeal I phalangeal II phalangeal III phalangeal IV Metacarpo-Proximal Proximal Proximal Inter- phalangeal V Interphalangeal IIInterphalangeal III phalangeal IV Proximal Inter- Knee phalangeal V

Leeds Dactylitis Index (LDI), Dactylitis Count and Tender DactylitisCount

The Dactylitis scores will be the presence of Dactylitis at baseline,the Dactylitis Count (out of subjects with baseline presence ofDactylitis) (“total dactylitis count” or “tender dactylitis count”) andthe resolution of Dactylitis (out of subjects with baseline presence ofDactylitis). The presence of Dactylitis at baseline is defined as thefollowing: at least one affected and tender digit with circumferenceincrease over reference digit≥10%. The Dactylitis Count will becalculated as the number of digits (hands and feet) with presence ofdactylitis, and ranges from 0 to 20.

The Leeds Dactylitis Index (LDI) is a score based on fingercircumference and tenderness, assessed and summed across all dactyliticdigits. The assessment should begin with visual inspection of the handsand feet. For each pair of digits in which one or both digits appeardactylitic, the circumference of the affected digits (both right andleft side) is assessed using a dactylometer. Additionally, the affecteddigit pairs are assessed for tenderness by squeezing the digital shaftmid-way between the metacarpophalangeal and proximal interphalangealjoints and is recorded as tenderness, yes or no. Tenderness should notbe assessed by squeezing the joint lines. For each of 20 digits of asubject, a digit final score needs to be calculated first. For anunaffected digit, the digit final score is set to be 0. For an affecteddigit, the digit final score is calculated as (A/B−1)*100*C if A/B≥1.1,and digit finals score=0 if A/B<1.1, where A denotes the circumferenceof the digit, B the reference circumference, and C the tenderness score.The reference circumference can be either the circumference of theunaffected contralateral digit if available, or from a reference tableif otherwise. For any digit without an available dactylometermeasurement the standard reference value will be utilized in calculationof the LDI. LDI is the sum of the digit final scores over all 20 digits.The proportion of subjects with Resolution of Dactylitis is defined asthe proportion of subjects with LDI=0. Digits injected withcorticosteroid will be considered non-evaluable for 90 days from thetime of the injection. If a digit is missing and its contralateral digitis dactylitic, “digit absent” will be recorded for the missing digit.

Enthesitis Scoring: Spondyloarthritis Research Consortium of Canada(SPARCC) Enthesitis Index, Leeds Enthesitis Index (LEI), TotalEnthesitis Count, and Maastricht Ankylosing Spondylitis Enthesitis Score(MASES)

For the Spondyloarthritis Research Consortium of Canada (SPARCC)Enthesitis Index, 16 sites are evaluated as indicated in rows 1-8 in thetable below. Tenderness on examination is recorded as either present(coded as 1), absent (coded as 0), or not assessed (NA) for each site.The SPARCC enthesitis index is calculated by taking the sum of thescores from the 16 sites. The SPARCC score ranges from 0 to 16.

The Leeds Enthesitis Index evaluates enthesitis at the 6 entheseal sitesindicated in rows 2, 7 and 9 in the table below. Tenderness onexamination is recorded as either present (coded as 1), absent (coded as0), or not assessed (NA) for each of the 6 sites. The LEI is calculatedby taking the sum of the scores from the 6 sites. The LEI ranges from 0to 6.

The Total Enthesitis Count is calculated by taking the sum of thetenderness scores from all 18 sites in the table below.

The proportion of subjects with resolution of enthesitis sites includedin the LEI is defined as the proportion of subjects with LEI=0; theproportion with resolution of the SPARCC Enthesitis Index and of thetotal enthesitis count are similarly defined (score=0).

TABLE 3 Tenderness in Left Tenderness in Right Present Absent NA PresentAbsent NA 1 Medial epicondyle 2 Lateral epicondyle 3 Supraspinatusinsertion into the greater tuberosity of humerus 4 Greater trochanterQuadriceps insertion into superior border of patella 6 Patellar ligamentinsertion into inferior pole of patella or tibial tubercle 7 Achillestendon insertion into calcaneum 8 Plantar fascia insertion intocalcaneum 9 Medial femoral condyle Present = 1; Absent = 0; NA = Notassessed

The Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) will bemeasured to assess the presence (1) or absence (0) of enthesitis at 13different sites (first costochondral joint left/right, seventhcostochondral joint left/right, posterior superior iliac spineleft/right, anterior superior iliac spine left/right, iliac crestleft/right, fifth lumbar spinous process, and proximal insertion ofAchilles tendon left/right), noting the subjects' responses, yielding atotal score ranging 0-13. If one or more locations are missing, thescore will be calculated using available data. If all locations aremissing, then MASES is set to be missing.

EuroQoL-5D (EQ-5D-5L)

The EQ-5D-5L questionnaire is one of the most commonly usedquestionnaires to measure health-related quality of life. It consists ofa questionnaire and a visual analogue scale (VAS). The self-assessmentquestionnaire measures 5 dimensions of health status (mobility,self-care, usual activities, pain/discomfort, and anxiety/depression).The AS subject is asked to grade their own current level of function ineach dimension into 1 of 3 degrees of disability (severe, moderate, ornone). The PsA subject is asked to grade their own current level offunction in each dimension into 5 levels per dimension (no problems,slight problems, moderate problems, severe problems, and extremeproblems corresponding to Level 1 to Level 5 respectively) and includesthe EQ Visual Analogue Scale (EQ VAS). The 5 dimensions of health statusare converted into a single index value. Using the VAS, subjects recordperceptions of current perceived health status with a grade ranging from0 (the worst possible health status) to 100 (the best possible healthstatus).

FACIT-Fatigue Questionnaire (FACIT-F)

The FACIT Fatigue Questionnaire is a 13-Question tool that measures anindividual's level of fatigue during their usual daily activities overthe past week. The level of fatigue is measured on a four point scale(4=not at all fatigued to 0=very much fatigued). The Fatigue scaleranges from 0 to 52, with higher scores indicating less fatigue.Question score for each Question is calculated by either subtractingfrom 4 or adding 0 depending on whether it is a reversal Question ornot. FACIT Fatigue Scale is then calculated by adding up all Questionscores, multiplying by 13 and dividing by the number of Questionsanswered. If less than 7 Questions are answered, the scale will not becomputed.

-   -   1. I feel fatigued    -   2. I feel weak all over    -   3. I feel listless (“washed out”)    -   4. I feel tired    -   5. I have trouble starting things because I am tired    -   6. I have trouble finishing things because I am tired    -   7. I have energy    -   8. I am able to do my usual activities    -   9. I need to sleep during the day    -   10. I am too tired to eat    -   11. I need help doing my usual activities    -   12. I am frustrated by being too tired to do the things I want        to do    -   13. I have to limit my social activity because I am too tired

Health Assessment Questionnaire Disability Index (HAO DI)

HAQ-DI is a self-reported patient outcome measurement. It is calculatedas the mean of the scores from 8 following categories with a range 0-3:Dressing and Grooming. Rising, Eating, Walking, Hygiene, Reach, Grip,and Activities. Higher scores reflect greater disability. The maximumscore for all the questions in each category is considered as the scorefor the category. The HAQ-DI takes into account the subject's use ofaids or devices or assistance in the scoring algorithm for a disabilitycategory. For each category there is an AIDS OR DEVICES companionvariable that is used to record the type of assistance, if any, asubject uses for his/her usual activities. If aids or devices and/orassistance from another person are checked for a category, the score forthis category is set to 2 (much difficulty), if the original score is 0(no difficulty) or 1 (some difficulty). The HAQ-DI is then calculated bysumming the adjusted categories scores and dividing by the number ofcategories answered. The HAQ-DI cannot be calculated if the subject doesnot have scores for at least 6 categories.

High-Sensitivity C Reactive Protein (hs-CRP)

C-reactive protein (CRP), which is measured in blood plasma, is an acutephase protein that appears in blood circulation in response toinflammation, and serves as a biomarker for systemic inflammation.However, routine methods of CRP detection (turbidimetric, nephelometric)demonstrated poor sensitivity in detecting concentrations of CRP below6-10 mg/litre. See, e.g., Poddubnyy et al., Ann. Rheum. Dis. (2010)69:1338-1341.

The high-sensitivity C-reactive protein (hs-CRP) assay is a more precisemeasurement than routine CRP. Several different tests may be used tomeasure the hs-CRP normal range versus abnormal value for the subject tobe treated; thus the upper limit of normal (ULN) will be determined bythe laboratory for the hs-CRP test used and may differ from laboratoryto laboratory.

Health Resource Utilization (HRU) Questionnaire for PsA

The HRU questionnaire contains three questions regarding health careutilization in the following categories: unscheduled health careprofessional visits, emergency room visits, and hospital admissions. Thedata gathered from the HRU questionnaire will be used to calculate theindividual cumulative number of utilizations per unit of time (e.g.,subject-year) under observation in each variable (i.e., the number ofunscheduled PsA-related health care professional visits, the number ofemergency room visits, the number of hospital admissions and the totalnumber of days in hospital) as follows: (i) time under observation for asubject will be defined as “date of last visit with non-missing HRU—dateof baseline visit.” and (ii) the number of utilizations after baselinewill be summed up for each subject.

Joint Count Assessment: SJC and TJC

Swollen Joint Count Assessment (SJC or SJC66): An assessment of 66joints will be done by physical examination. The joints to be examinedfor swelling are the same as those examined for tenderness, except thehip joints are excluded. Joint swelling will be classified as present(“1”), absent (“0”), replaced (“9”), or no assessment (“NA”). Jointsinjected with corticosteroid will be considered non-evaluable for 90days from the time of the injection. The range for SJC66 will be 0 to66.

Tender Joint Count Assessment (TJC or TJC68): An assessment of 68 jointswill be done for tenderness by pressure manipulation on physicalexamination. Joint pain/tenderness will be classified as: present (“1”),absent (“0”), replaced (“9”), or no assessment (“NA”). Joints injectedwith corticosteroid will be considered non-evaluable for 90 days fromthe time of the injection. The range for TJC68 will be 0 to 68.

Anatomical joints are evaluated for swelling and tenderness at everystudy visit. The 34 anatomical joints in the below table are assessed inthis study for both the left and right side of the body.

TABLE 4 Anatomical Joints Assessed for Calculation of Tender and SwollenJoint Counts (TJC68 and SJC66) Temporomandibular SternoclavicularAcromio-clavicular Shoulder Elbow Wrist Metacarpophalangeal IMetacarpophalangeal II Metacarpophalangeal MetacarpophalangealMetacarpophalangeal V Thumb Interphalangeal III IV Proximal ProximalProximal Proximal Interphalangeal II Interphalangeal III interphalangealIV interphalangeal V Distal Distal Distal Distal Interphalangeal IIinterphalangeal III interphalangeal IV interphalangeal V Hip^(a) KneeAnkle Tarsus Metatarsophalangeal I Metatarsophalangeal IIMetatarsophalangeal III Metatarsophalangeal IV Metatarsophalangeal VGreat Toe/Hallux Interphalangeal II Interphalangeal III InterphalangealIV Interphalangeal V ^(a)Hip joints are not assessed for swelling.Modified Stoke Ankylosing Spondylitis Spine Score (mSASSS)

The mSASSS is a scoring method that measure radiographic progression inthe spine of patients with ankylosing spondylitis. The mSASSS has arange of 0 to 72, which is derived from scoring the anterior site of thelumbar spine from the lower border of T12 to the upper border of S1 andthe anterior site of the cervical spine from the lower border of C2 tothe upper border of T1 as either 0 (normal), 1 (erosion, sclerosis, orsquaring), 2 (syndesmophyte), 3 (bridging syndesmophyte), or NAvertebral body not evaluable. X-ray of spinal films will be analyzed forradiographic progression (from Baseline to the follow-up timepoint).

Modified Psoriatic Arthritis Response Criteria (Modified PsARC)

The modified PsARC is a PsA-specific composite responder index. Toachieve response, a subject must achieve 2 of the following 4 Questions,one of which has to be a Tender Joint Count 68 or Swollen Joint Count66, and no worsening of any measure: ≥30% improvement in TJC68; ≥30%improvement in SJC66; Improvement in PtGA of Disease Activity NRS;Improvement in PGA of Disease Activity NRS.

Patient's Assessment of Nocturnal Back Pain (Nocturnal Back Pain),Patient's Assessment of Total Back Pain (Total Back Pain score), andPatient's Global Assessment of Pain (Pt Pain or “Pain”) Numerical RatingScales (NRS)

Pain will be measured using 0-10 numerical rating scale (NRS) scaleQuestions for Nocturnal Back Pain NRS (0=no pain and 10=worst possiblepain), Total Back Pain (0=no pain and 10=severe pain), and Pain (i.e.,overall pain) (0=no pain and 10=severe pain).

ASAS (e.g., ASAS20, ASAS40, ASAS PR) assesses the Patient's Assessmentof Total Back Pain (Total Back Pain score) using the above describedscoring method. For ASDAS, Patient's Assessment of Total Back Painassesses total back pain by answering BASDAI Question 2.

Psoriatic Arthritis Disease Activity Score (PASDAS)

PASDAS is a continuous scale of combined joint, dactylitis andenthesitis assessments, physician and patient global assessments forarthritis, SF36-PCS, and hsCRP measurements. PASDAS is calculated basedon the following equation:

=(((0.18√(PGA))+0.159√(PtGA)−0.253√(SF36-PCS)+0.101 ln(SJC66+1)+0.048 ln(TJC68+1)+0.23 ln(LEI+1)+0.37 ln(Tender Dactylitis Count+1)+0.102ln(hsCRP+1)+2)*1.5

wherein √ is square root and in is natural log; PtGA is on the scale of0-10; PGA is on the scale of 0-100 (as PtGA and PGA are collected withthe scale of 0-10 NRS, their values need to be multiplied by 10 beforebeing used in the PASDAS formula); SF36-PCS is the physical componentscale in the SF36 instrument; the unit for hsCRP is mg/L; and LEI rangesfrom 0 to 6.

Psoriasis Area Severity Index (PASI)

The PASI is a measure of psoriasis severity. Four anatomic sites—head,upper extremities, trunk, and lower extremities—are assessed forerythema, induration and desquamation using a 5-point scale (0=nosymptoms; 1=slight; 2=moderate; 3=marked; 4=very marked). Based on theextent of lesions in a given anatomic site, the area affected isassigned a numerical value (0=no involvement; 1=<10%; 2=10%-29%;3=30%-49%; 4=50%-69%; 5=70%-89%; 6=90%-100%). Since the head, upperextremities, trunk and lower extremities correspond to approximately 10,20, 30 and 40% of body surface area, respectively; the PASI score iscalculated using the formula:

=0.1(E _(h) +I _(h) +D _(h))A _(h)+0.2(E _(u) +I _(u) +D _(u))A_(u)+0.3(E _(t) +I _(t) +D _(t))A _(t)+0.4(E _(l) +I _(l) +D _(l))A _(l)

where E, I, D, and A denote erythema, induration, desquamation, andarea, respectively, and h, u, t, and l denote head, upper extremities,trunk, and lower extremities, respectively.

PASI scores range from 0.0 to 72.0 with the highest score representingcomplete erythroderma of the severest possible degree. Typically scoresof 3 or less represent mild disease, scores over 3 and up and including15 represent moderate disease and scores over 15 are considered to beassociated with severe disease. If a Question is missing, PASI is notscored. PASI 75 (PASI 50, PASI 90, PASI 100) response is achieved ifthere is at least a 75% (50%, 90%, 100%) reduction in PASI score (≥PASI75/50/90/100 response) at a visit relative to the Baseline PASI score.See, e.g., Feldman et al., J Invest Dermatol. 1996; 106(1):183-6.

Self-Assessment of Psoriasis Symptoms (SAPS)

The Self-Assessment of Psoriasis Symptoms (SAPS) contains 11symptom-focused Questions, as provided below. Each Question is scoredfrom 0 to 10, with 0 being least severe and 10 being most severe. Thetotal score is generated by summing the 11 Questions.

The total score ranges from 0 to 110.

-   -   1. Over the past 24 hours, what was the worst pain you        experienced in the areas affected by psoriasis?    -   2. Over the past 24 hours, what was the worst itching you        experienced in the areas affected by psoriasis?    -   3. Over the past 24 hours, what was the worst redness you        experienced in the areas affected by psoriasis?    -   4. Over the past 24 hours, what was the worst scaling you        experienced in the areas affected by psoriasis?    -   5. Over the past 24 hours, what was the worst flaking (scales        falling off your skin) you experienced in the areas affected by        psoriasis?    -   6. Over the past 24 hours, what was the worst bleeding you        experienced in the areas affected by psoriasis?    -   7. Over the past 24 hours, what was the worst burning you        experienced in the areas affected by psoriasis?    -   8. Over the past 24 hours, what was the worst stinging you        experienced in the areas affected by psoriasis?    -   9. Over the past 24 hours, what was the worst tenderness you        experienced in the areas affected by psoriasis?    -   10. Over the past 24 hours, what was the worst pain you        experienced due to skin cracking in the areas affected by        psoriasis?    -   11. Over the past 24 hours, what was the worst joint pain you        experienced due to psoriasis?        Sharp/Van Der Heijde Score (SHS) Score (Equivalent to the        Modified Total Sharp Score, mTSS)

Radiographic outcomes will be assessed and scored according to Sharp'smethod (van der Heijde modification for PsA). To obtain the total SHSscore, scores for erosions and JSN in both the hands and feet will beadded together. The range of scores is summarized below. A finding of NoRadiographic Progression of PsA is no change or improvement frombaseline in SHS (≤0).

TABLE 5 Range of Total SHS Score, Erosion Score and Joint SpaceNarrowing Total Hands Feet (Hands and Feet) Erosion Score Range 0-2000-120 0-320 Joint Space Narrowing Range 0-160 0-48  0-208 Total SHSRange for 0-360 0-168 0-528 Erosion and JSN

Erosion Assessment. Erosions will be assessed in each hand (20 locationsper hand) and foot (6 locations per foot). The locations assessed in theSHS method include: 4 Distal inter-phalangeal joints (2-5); 5Metacarpo-Phalangeal Joints (1-5); 4 Proximal Inter-Phalangeal Joints(2-5); Inter-Phalangeal Joint of the thumb; Proximal first MetacarpalBone; Radius Bone; Ulnar Bone; Trapezium and Trapezoid (as one unit;multangular); Navicular Bone; Lunate Bone; 5 Metatarso-phalangeal joints(1-5); Inter-phalangeal joint of the first toe.

Joint Space Narrowing Assessment. Joint space narrowing (JSN) will beassessed in each hand (20 locations per hand) and foot (6 locations perfoot). The locations assessed in the SHS method include: 4 Distalinter-phalangeal joints (2-5); 4 Proximal inter-phalangeal joints (2-5);5 Metacarpo-phalangeal joints (1-5); Interphalangeal Joint of thumb(IP); 3 Carpo-metacarpal joints (3-5); Radio-carpal joint;Multangular-navicular joint; Capitate-navicular-lunate joint; 5Metatarso-phalangeal joints; Inter-phalangeal joint of first toe.

For each Joint and Bone assessed, scores range as follows: Erosions: 0-5(hands/wrists) or 0-10 (feet) to characterize the extent of erosions(where 0 denotes no erosion); Joint Space Narrowing: 0-4 to characterizethe extent of Joint Space Narrowing (JSN) (where 0 denotes nonarrowing).

SpondyloArthritis Research Consortium of Canada (SPARCC) Assessment forSpine (MRI SPARCC—Spine or MRI-Spine SPARCC) and Sacroiliac (SI) Joints(MRI SPARCC—Joints or MRI-SI Joints SPARCC)

SPARCC scores for spine and sacroiliac (SI) joints are calculated byadding up the dichotomous outcomes from evaluations of the presence,depth and intensity of bone marrow edema lesions of the spine and SIjoints, respectively.

In the MRI SPARCC score of Spine, the entire spine is evaluated foractive inflammation (bone marrow edema) using the Short-TI InversionRecovery (STIR) image sequence. 23 discovertebral units (DVUs) areassessed, and the six most severely affected DVUs are selected and usedto calculate the MRI Spine SPARCC score. For each of the six DV Us, 3consecutive sagittal slices are assessed in four quadrants in order toevaluate the extent of inflammation in all three dimensions.

-   -   1. Each quadrant is scored for presence of increased signal on        STIR (1=increased signal; 0=normal signal)    -   2. Presence, on each of the sagittal slices, of a lesion        exhibiting high signal intensity (comparable to cerebrospinal        fluid) in any disco-vertebral unit is given an additional score        of 1.    -   3. Slices that included a lesion demonstrating continuous        increased signal of depth≥1 cm extending from the endplate are        to be scored as +1 per slice.

The maximum possible score for any individual slice is 6, with a maximumscore for all 6 discovertebral units being 108.

The MRI SPARCC score of SI joints is conducted on 6 consecutive slicesof the STIR image sequence. All lesions within the iliac bone and withinthe sacrum up to the sacral foramina are to be scored. The SI joint isdivided into 4 quadrants: upper iliac, lower iliac, upper sacral andlower sacral. Each consecutive slice is scored separately for the rightand left joint in all four quadrants as follows:

-   -   1. Each quadrant is scored for presence of increased signal on        STIR (1=increased signal: 0=normal signal)    -   2. Joints that include a lesion exhibiting intense signal on the        STIR sequence are scored as +1 per slice.    -   3. Joints that included a lesion demonstrating continuous        increased signal of depth≥1 cm from the articular surface are be        scored as +1 per slice.

The maximum possible score for any individual slice is 12, with amaximum score for all 6 slices being 72.

Static Investigator Global Assessment of Psoriasis (sIGA)

The sIGA is a 5-point score ranging from 0 to 4, based on assessment ofthe average elevation, erythema, and scaling of all psoriatic lesions.The assessment is considered “static” which refers to the patient'sdisease state at the time of the assessments, without comparison to anyof the patient's previous disease states, whether at baseline or at aprevious visit. A lower score indicates less severe psoriasis (0=clear,1=almost clear, 2=mild, 3=moderate and 4=severe). A binary clinicalendpoint for the PsA-1 and PsA-2 clinical studies based on sIGA is theproportion of subjects achieving a sIGA score of 0 or 1 and at least a2-point improvement from baseline. This endpoint is calculated among thesubjects with baseline sIGA score≥2.

Work Productivity and Activity Impairment Questionnaire for PsoriaticArthritis (WPAI-PsA) and Axial Spondyloarthritis (WPAI-Axial SpA)

The Work Productivity and Activity Impairment Questionnaire (WPAI) wasdeveloped to measure the effect of overall health and specific symptomson productivity at work and outside of work. It consists of 6 questions.A lower WPAI score indicates an improvement. The 4 main impairmentscores (S1 to S4) are expressed as percent impairment based on the 6questions.

-   -   S0. Employment: defined below    -   S1. Absenteeism: Percent work time missed due to PsA or Axial        SpA:

$100 \times \left\lbrack \frac{Q\; 2}{{Q\; 2} + {Q\; 4}} \right\rbrack$

-   -   S2. Presenteeism: Percent impairment while working due to PsA or        Axial SpA:

$100 \times \left\lbrack \frac{Q\; 5}{10} \right\rbrack$

-   -   S3. Percent overall work impairment due to PsA or Axial SpA:

$100 \times \left\lbrack {\frac{Q\; 2}{{Q\; 2} + {Q\; 4}} + {\left\{ {1 - \frac{Q\; 2}{{Q\; 2} + {Q\; 4}}} \right\} \times \frac{Q\; 5}{10}}} \right\rbrack$

-   -   S4. Percent activity impairment due to PsA or Axial SpA:

$100 \times \left\lbrack \frac{Q\; 6}{10} \right\rbrack$

-   -   S5. Did subject miss work (defined below). This is needed to        derive the proportion of subjects who missed work.

When calculating the WPAI scores, the following computational notesshould be followed.

-   -   Define Employment as a binary YES or NO variable where YES        corresponds to “Employed” and NO corresponds to “Not Employed.”    -   A subject will be considered “employed” at a given visit if        Q1=YES or Q2>0 or Q4>0.    -   A subject will be considered “unemployed” at a given visit if        Q1=NO and no positive hours recorded under Q2 and Q4 (i.e., if        Q1=NO AND Q2≤0 AND Q4≤0, then UNEMPLOYED).    -   Employment status for a subject will be considered “missing” at        a given visit if Q1=missing and no positive hours recorded under        Q2 and Q4.    -   If a subject is “unemployed” or employment status is “missing,”        then S1, S2, and S3 will be set to “missing.”    -   If Q2=0 and Q4=0 or missing then Q2/(Q2+Q4)=missing (i.e.,        SI=missing).    -   If Q2=0 and Q4=0, then set S3 to missing.    -   If Q2 is missing or Q4 is missing, then set S1 and S3 to        missing.    -   If Q4=missing, then DO NOT set Q5=missing.    -   If Q5 is missing, then apply the following rules:    -   If Q2>0, Q4=0, and Q5=missing, then S3=100%.    -   If Q2=0, Q4>0, and Q5=missing, then S3 is missing.    -   If Q2>0, Q4>0, and Q5=missing, then S3 is missing.    -   Determine if a subject missed work (based on Q2) in order to        analyze the proportion of subjects who missed work:    -   Create a binary (yes or no) “missed work” variable.    -   A subject will be considered as yes to missed work if Q2 is        greater than 0.    -   If Q2=missing, then MISSED WORK=missing.    -   If Q2>0, then MISSED WORK=“yes.”    -   If Q2=0, then MISSED WORK=“no.”    -   Therefore, the proportion of subjects who missed work will be        counted based on the number of subjects with MISSED WORK=YES.

36-Item Short Form Health Survey (Form SF-36)

The 36-Item Short Form, Version 2 (SF-36v2) (Quality Metric) healthsurvey consists of 36 general health questions. It has 2 components:physical and mental. For each component, a transformed summary score iscalculated using 8 sub domains: physical functioning, role-physical,bodily pain, general health, vitality, social functioning,role-emotional, and mental health. The range is from 0 to 100, withhigher scores indicating better outcomes. The coding and scoring for theSF-36 will use the software provided by the vendor.

Additional Definitions

A “subject” means a human. The terms “patient” and “subject” are usedinterchangeably herein.

An “adult subject” means a subject 18 years or older.

A “juvenile” or “pediatric” subject means a subject 1 to <18 years old.Juvenile subjects to be treated are subjects diagnosed with juvenile AS(JAS), juvenile PsA (JPsA), and/or juvenile PsO (JPsO) and in need oftreatment as determined by a physician (“active juvenile AS” and “activejuvenile PsA”, “active juvenile PsO”, respectively). Juvenile AS may beclassified per International League of Associations for Rheumatology(ILAR) (defining 7 discrete categories of arthritis starting before theage of 18 years: systemic arthritis, oligoarthritis, polyarthritis(rheumatoid factor [RF]-negative), polyarthritis (RF-positive), PsA,enthesitis-related JIA (or juvenile enthesitis-related arthritis [ERA]),and undifferentiated arthritis). See, e.g., Petty el al., J Rheumatol.(2004)31:390-2. Juvenile PsA may be classified per pediatricInternational League of Associations for Rheumatology (ILAR) and/oradult criteria [Classification criteria for Psoriatic Arthritis(CASPAR)]. See e.g., Aviel et al., Pediatric Rheumatology (2013) 11:11;Zisman et al., J Rheum. (2017) 44:342-351.

The “2009 ASAS classification criteria” for the classification of asubject with axial spondyloarthritis (axial SpA, or axSpA) is describedin Rudwaleit el al., Ann. Rheum. Dis. (2009) 68:777-783. The criteriarequire chronic back pain (≥3 months) in the subject and age at onset<45 years, with the subject also having the following conditions (1) thepresence of sacroiliitis by radiography or by magnetic resonance imaging(MRI) plus at least one SpA feature (“imaging arm”) or (2) the presenceof human leukocyte antigen (HLA) B27 plus at least two SpA features(“clinical arm”). Sacroiliitis on imaging refers to active (acute)inflammation on MRI highly suggestive of sacroiliitis associated withSpA, or definite radiographic sacroiliitis. SpA features are selectedfrom the group consisting of inflammatory back pain, arthritis,enthesitis (heel), uveitis, dactylitis, psoriasis, Crohn's disease orulcerative colitis, good response to NSAISs (24-48 hours after a fulldose of an NSAID the back pain is not present any more or is muchbetter), family history for SpA, positive HLA-B27, and elevatedC-reactive protein (above the upper normal limit in the presence of backpain, and after exclusion of other reasons for elevation). See alsoDeodhar et al., Arth. & Rheum. (2014) 66:2649-2656.

The “1984 modified New York criteria” for the classification of asubject with ankylosing spondylitis (AS), is described in van der Lindenet al., Arthritis and Rheumatism (1984) 27:361-368, and has twocomponents: diagnosis and grading; the diagnosis component further hastwo criteria: clinical and radiologic. The clinical criteria require:(i) low back pain and stiffness for more than 3 months which improveswith exercise, but is not relieved by rest; (ii) limitation of motion ofthe lumbar spine in both the sagittal and frontal planes, and (iii)limitation of chest expansion relative to normal values corrected forage and sex. The radiologic criterion requires sacroiliitis grade≥2bilaterally or sacroiliitis grade 3-4 unilaterally. The gradingcomponent requires: (i) definite ankylosing spondylitis if theradiologic criterion is associated with at least 1 clinical criterion;and (ii) probable ankylosing spondylitis if 3 clinical criteria arepresent, and the radiologic criterion is present without any signs orsymptoms satisfying the clinical criteria. See also Deodhar et al.,Arth. & Rheum. (2014) 66:2649-2656.

The term “axial Spondyloarthritis” (axial SpA or axSpA) encompasses both“ankylosing spondylitis” (AS) and “non-radiographic axialspondyloarthritis” (nr-axial SpA, or nr-axSpA). A subject with “activeaxial Spondyloarthritis” (active axSpA) means a subject with a clinicaldiagnosis of active AS or active nr-axial SpA, and in need of treatmentas determined by a physician.

A subject with “active ankylosing spondylitis” (active AS) means asubject with a clinical diagnosis of AS and in need of treatment asdetermined by a physician. In certain embodiments, the subject diagnosedas suffering from AS is further classified (e.g., in the United States)as fulfilling the 1984 modified New York Criteria for AS and/or asfulfilling the 2009 ASAS classification criteria. In certainembodiments, the subject with a high disease activity of AS has a BathAnkylosing Spondylitis Disease Activity Index score≥4 and/or ASDAS≥2.1and/or a Patient's Assessment of Total Back Pain (Total Back Painscore)≥4 based on a 0-10 numerical rating scale at baseline. See, e.g.,van der Heijde et al., Ann Rheum Dis. (2017)76:978-991; Sieper andPoddubnyy. Lancet (2017) 73-84.

A subject with “active non-radiographic axial spondyloarthritis” (activenr-axial SpA or active nr-axSpA) means a subject with a clinicaldiagnosis of nr-axial SpA and in need of treatment as determined by aphysician. In certain embodiments, the subject diagnosed as sufferingfrom nr-axial SpA is further classified (e.g., in the United States) asfulfilling the 2009 ASAS classification criteria for axSpA but notmeeting the radiologic criterion of the 1984 modified New York criteriafor AS. In certain embodiments, the subject with high disease activityof nr-axial SpA has a Bath Ankylosing Spondylitis Disease Activity Indexscore≥4 and/or an ASDAS≥2.1 and/or a Patient's Assessment of Total BackPain Score (Total Back Pain score)≥4 based on a 0-10 numerical ratingscale at baseline; and an objective sign of inflammatory activityselected from the group consisting of (i) an objective sign of activeinflammation on MRI of SI joints or (ii) hsCRP>upper limit of normal(ULN) at baseline. See, e.g., van der Heijde et al., Ann Rheum Dis.(2017) 76:978-991 Sieper el al. Ann. Rheum. Dis. (2009) 68 Suppl2:ii1-44. doi: 10.1136/ard.2008.104018; Van der Heijde et al. Ann RheumDis. (2017) 76:978-991; Sieper and Poddubnyy. Lancet (2017) 73-84.

The “CASPAR criteria” (Classification criteria for Psoriatic Arthritis(see, e.g., Taylor et al., Arthritis and Rheumatism (2006)54:2665-2673)) requires the subject to have inflammatory articulardisease (joint, spine, or entheseal) with ≥3 points from the following 5categories at baseline:

-   -   1. Evidence of current psoriasis, a personal history of        psoriasis, or a family history of psoriasis (one of the        following).        -   a. Current psoriasis is defined as psoriatic skin or scalp            disease present today as judged by a rheumatologist or            dermatologist. Current psoriasis is assigned a score of 2;            all other features are assigned a score of 1.        -   b. A personal history of psoriasis is defined as a history            of psoriasis that may be obtained from a patient, family            physician, dermatologist, rheumatologist, or other qualified            health care provider.        -   c. A family history of psoriasis is defined as a history of            psoriasis in a first- or second-degree relative according to            a patient report.    -   2. Typical psoriatic nail dystrophy including onycholysis,        pitting, and hyperkeratosis observed on current physical        examination.    -   3. A negative test result for the presence of rheumatoid factor        by any method except latex but preferably by enzyme-linked        immunosorbent assay or nephelometry, according to the local        laboratory reference range.    -   4. Either current dactylitis, defined as swelling of an entire        digit, or a history of dactylitis recorded by a rheumatologist.    -   5. Radiographic evidence of juxta articular new bone formation,        appearing as ill-defined ossification near joint margins (but        excluding osteophyte formation) on plain radiographs of the hand        or foot.

A subject with “active psoriatic arthritis” (active PsA) means a subjectwith a clinical diagnosis of PsA and in need of treatment as determinedby a physician. In certain embodiments, the subject diagnosed assuffering from PsA is further classified (e.g., in the United States) asfulfilling the Classification Criteria for PsA (CASPAR) criteria atbaseline. In certain embodiments, the subject may have ≥3 tender joints(based on 68 joint counts) and ≥3 swollen joints (based on 66 jointcounts) at baseline. In certain embodiments, the subject may have ≥5tender joints (based on 68 joint counts) and ≥5 swollen joints (based on66 joint counts) at baseline. In certain embodiments, the subject mayhave ≥3% Body Surface Area with Psoriasis (BSA-PS). In certainembodiments, subjects with Minimal Disease Activity (responders andnon-responders) for PsA are excluded. “Active PsA” includes subjects whoare, as determined by a physician, functioning normally while sufferingfrom active PsA and subjects who are not, as determined by a physician,functioning normally while suffering from active PsA. For example, asubject with psoriasis on the abdomen may be considered to bemanifesting active PsA but able to function normally, while a subjectwith psoriasis on the face may be considered to be manifesting activePsA but not able to function normally (e.g., due to emotional distress).“Moderately to severely active PsA” is a subset of “active PsA” andinvolves the determination by a physician that the subject is not ableto function normally while suffering from active PsA.

A subject with “active psoriasis” (active PsO) means a subject with aclinical diagnosis of PsO and in need of treatment as determined by aphysician. In certain embodiments, the active psoriasis is active plaquepsoriasis. In certain embodiments, the subject has a documented historyof plaque psoriasis. “Active PsO” includes subjects who are, asdetermined by a physician, functioning normally while suffering fromactive PsO and subjects who are not, as determined by a physician,functioning normally while suffering from active PsO. For example, asubject with psoriasis on the abdomen may be considered to bemanifesting active PsO but able to function normally, while a subjectwith psoriasis on the face may be considered to be manifesting activePsO but not able to function normally (e.g., due to emotional distress).“Moderately to severely active PsO” is a subset of “active PsO” andinvolves the determination by a physician that the subject is not ableto function normally while suffering from active PsO. In certainembodiments, the subject may have ≥3% Body Surface Area with Psoriasis(BSA-PS) at baseline.

The abbreviation “AS” refers to ankylosing spondylitis.

A result being achieved “within X weeks” of administration of the firstdose of the JAK1 inhibitor wherein X is a integer greater than 0 (e.g.,1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 52, . . . 64 weeks, etc.)means the result occurs within the time frame beginning at the time ofthe administration of the first dose (Week 0) of the JAK1 inhibitor, andending on and including the last day of the given specified week. Ameasurement or score used to determine if a result is achieved “at weekX” (e.g., at week 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 52, . .. 64 weeks, etc.) may be taken at any point during, as well as on andincluding the first and last day, of given week X for the subject.

The abbreviation “axSpA” refers to axial spondyloarthritis.

The abbreviations “bDMARDs” and “biologic DMARDs” refer to biologicDisease Modifying Anti-Rheumatic Drugs. Examples of bDMARDs include, butare not limited to, biologic tumor necrosis factor inhibitors (e.g.,adalimumab, etanercept) and interleukin (IL)-17 inhibitors (e.g.,secukinumab, ixekizumab).

The term “bDMARD-IR” refers to a subject who is a bDMARD inadequateresponder. bDMARD-IR subjects include those who have had an inadequateresponse to treatment with at least one bDMARD, or who have anintolerance to or contraindication for bDMARDs. Subjects who arebDMARD-IR include subjects who have discontinued treatment with at leastone bDMARD due to intolerance or lack of efficacy.

The term “bDMARD naïve” refers to a subject who has not had priorexposure to any biologic therapy, including any bDMARD, that maypotentially have a therapeutic impact on the disorder or condition thatis being treated.

The term “baseline” or “BL” refers to the time immediately before firstdosing with the JAK1 inhibitor. Baseline measurements (i.e., on the“Baseline Visit” or on the “Screening Visit”) are collected prior toadministration of the first dose of the JAK1 inhibitor (i.e.,upadacitinib freebase or a pharmaceutically acceptable salt thereof),and may include a measurement taken the day of but prior to first dosingwith the JAK1 inhibitor.

The term “change from baseline” for a particular score or measurementmeans the score or measurement has improved (e.g., demonstrating apositive clinical effect in the subject or population of subjects) ascompared to the score or measurement taken at baseline.

The abbreviation “CII” means Clinically Important Improvement.

The phrase “concomitant administration” or “concomitant treatment” whenreferencing a therapy in addition to administration of the JAK1inhibitor means the additional therapy is occurring at baseline and/orduring treatment with the JAK1 inhibitor.

The abbreviations “DMARDs” and “non-biologic DMARDs” refer tonon-biologic Disease Modifying Anti-Rheumatic Drugs. Non-biologic DMARDsinclude, but are not limited to, methotrexate (MTX), sulfasalazine(SSZ), leflunomide (LEF), apremilast, hydroxychloroquine (HCQ),bucillamine, and iguratimod. “Non-biologic DMARDs” and“conventional-synthetic disease modifying anti-rheumatic drugs”(csDMARDs) are used interchangeably herein.

The term “DMARD-IR” or “non-biologic DMARD-IR” refers a subject who is anon-biologic DMARD inadequate responder. DMARD-IR subjects include thosewho have had an inadequate response to treatment with at least onenon-biologic DMARD, or who have an intolerance to or contraindicationfor non-biologic DMARDs.

The abbreviation “EMA” means European Medicines Agency.

The abbreviation “FDA” means Food and Drug Administration.

The abbreviation “hsCRP” means high-sensitivity C-reactive protein.

The abbreviation “ID” means Inactive Disease.

The phrase “improving physical function” in a subject with active PsAmeans an improvement in activities or tasks compared to baseline.

“In need of treatment” or “in need of treatment . . . as determined by aphysician” refers to the physician's opinion that, at baseline, thecondition is not sufficiently well-controlled, such as by other medicalmanagement (e.g., by other therapy or therapies previously administeredto treat the condition).

The phrase “inhibiting the progression of structural damage” or“preventing structural progression” in a subject with active PsA meansdemonstrating prevention of bony changes on x-ray compared to baseline.

“JAK1 inhibitor” refers to the compound upadacitinib((3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide)freebase or a pharmaceutically acceptable salt thereof. Solid stateforms of the JAK1 inhibitor are further described herein.

The abbreviation “LDA” means low disease activity.

The abbreviation “MI” means major improvement.

The abbreviation “MRI” means magnetic resonance imaging.

A result is considered “non-inferior” (NI) as compared to adalimumab ifadministration of the JAK1 inhibitor preserves at least 50% of theplacebo-subtracted adalimumab effect.

The abbreviation “nr-axSpA” refers to non-radiographic axialspondyloarthritis.

The abbreviation “NRI” means non-responder imputation.

The abbreviation “NSAIDs” refers to non-steroidal anti-inflammatorydrugs. Examples NSAIDs include, but are not limited to, traditionalNSAIDs (e.g., ibuprofen) and salicylates (e.g., aspirin).

The term “pharmaceutically acceptable” (such as in the recitation of a“pharmaceutically acceptable salt” or a “pharmaceutically acceptablediluent”) refers to a material that is compatible with administration toa human subject. e.g., the material does not cause an undesirablebiological effect. Examples of pharmaceutically acceptable salts aredescribed in “Handbook of Pharmaceutical Salts: Properties, Selection,and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim. Germany, 2002).Examples of pharmaceutically acceptable excipients are described in the“Handbook of Pharmaceutical Excipients,” Rowe et al., Ed.(Pharmaceutical Press, 7th Ed., 2012).

“Pharmaceutically acceptable salts” refers to those salts which retainthe biological effectiveness and properties of the free bases and whichare obtained by reaction with inorganic acids, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acidor organic acids such as sulfonic acid, carboxylic acid, organicphosphoric acid, methane sulfonic acid, ethane sulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid,benzoic acid, salicylic acid, lactic acid, mono-malic acid, mono oxalicacid, tartaric acid such as mono tartaric acid (e.g., (+) or(−)-tartaric acid or mixtures thereof), amino acids (e.g., (+) or(−)-amino acids or mixtures thereof), and the like. These salts can beprepared by methods known to those skilled in the art.

A “population of subjects” refers to the group of subjects participatingin a clinical trial, with all subjects suffering from the same diseaseor symptom to be treated, wherein the clinical trial comprises atreatment arm (a subgroup of the subjects treated with the JAK1inhibitor), and a placebo arm (a subgroup of the subjects not treatedwith the JAK1 inhibitor). When used in connection with the treatment ofa population of subjects, the phrase “at least X % of the subjects inthe treated population achieve” a particular response refers to theplacebo corrected X % response (subjects treated−subjects not treated).

The abbreviation “PR” means partial remission.

The abbreviation “PsA” refers to psoriatic arthritis.

The abbreviation “PsO” refers to psoriasis. Psoriasis includes psoriasisas a skin manifestation of PsA.

The abbreviation “QD” means once daily.

The phrase “reducing signs and symptoms” means an improvement in diseaseactivity, function, and/or quality of life compared to baseline.

The abbreviation “SI” means sacroiliac.

“Statistically significant” means when observed p value<alpha for agiven hypothesis testing. The pre-specified significance level, alpha,is the probability of rejecting the null hypothesis given that it istrue. Alpha is also called type 1 error or false positive rate. It isusually set at or below 0.05. The observed p value is the probability,under the null hypothesis, of observing an effect of the same magnitudeor more extreme. When observed p value<alpha, the null hypothesis isrejected, and statistical significance is claimed. In amultiplicity-controlled analysis, when the adjusted p value<alpha, theresult is statistically significant. In the fixed sequence of amultiplicity-controlled analysis, statistical significance can beclaimed for a lower ranked endpoint only if the previous endpoint in thesequence meets the requirements of statistical significance.

A result is considered “superior” as compared to adalimumab if themultiplicity adjusted p value for the null hypothesis testing of thetreatment difference between the JAK1 inhibitor and adalimumab is lessthan pre-specified significance level.

“Total spinal ankylosis” refers to bridging syndesmophytes (fusion) in atotal sum of ≥5 segments of the C2-T1 or T12-S1 spine (e.g., 2 segmentsfused in the cervical and 3 segments fused in the lumbar spine would beconsidered positive for total spinal ankylosis).

The terms “treating”, “treatment”, and “therapy” and the like, as usedherein, are meant to include but not limited to alleviation or relief ofone or more symptoms of the condition from which the subject issuffering (i.e., axial spondyloarthritis (axSpA) (e.g., non-radiographicaxSpA (nr-axSpA), ankylosing spondylitis (AS)), psoriatic arthritis(PsA), psoriasis (PsO)), including the slowing or cessation of theprogression of the condition, such as slowing or cessation of theprogression of structural damage associated with the condition, thestructural progression of the condition, and/or improving the physicalfunction of a subject suffering from the condition.

The term “upadacitinib freebase” refers to freebase (non-salt, neutral)forms of upadacitinib. Examples of upadacitinib freebase solid stateforms include amorphous upadacitinib freebase and crystalline freebasesof upadacitinib, such as crystalline freebase solvates, crystallinefreebase hydrates, crystalline freebase hemihydrates, and crystallinefreebase anhydrates of upadacitinib. Specific examples of upadacitinibfreebase solid state forms include but are not limited to AmorphousUpadacitinib Freebase, Upadacitinib Freebase Solvate Form A,Upadacitinib Freebase Hydrate Form B. Upadacitinib Freebase Hydrate FormC (which is a hemihydrate), and Upadacitinib Freebase Anhydrate Form D,each as described in WO 2017/066775 and WO 2018/165581.

The term “upadacitinib freebase equivalent” refers to the amount of theneutral upadacitinib freebase (active ingredient) administered, and notincluding any coformer (e.g., solvent or water molecule(s)) of a solvateor hydrate (including hemihydrate), and not including anypharmaceutically acceptable salt counter anions of a pharmaceuticallyacceptable salt. For example, 15.4 mg of crystalline upadacitinibfreebase hemihydrate (which includes ½ of a water conformer molecule perupadacitinib freebase molecule) delivers 15 mg of upadacitinib freebaseequivalent, while 30.7 mg of crystalline upadacitinib freebasehemihydrate (which includes ½ of a water conformer molecule perupadacitinib freebase molecule) delivers 30 mg of upadacitinib freebaseequivalent.

II. Methods of Treatment

The present disclosure also relates to methods of treating aJAK-associated condition in a subject, particularly a human subjectsuffering from or susceptible to the condition, comprising administeringto the subject a therapeutically effective amount of Compound 1 freebaseor a pharmaceutically acceptable salt thereof or one or more solid stateforms of Compound 1 as described in the present disclosure. Anotheraspect of the disclosure relates to Compound 1 freebase or apharmaceutically acceptable salt thereof or one or more solid stateforms of Compound 1 as described in the present disclosure for use intreatment of a JAK-associated condition in a subject, particularly in ahuman subject suffering from or susceptible to the condition, the usecomprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or one or more solid state forms of Compound 1. In one aspect,the condition is a JAK-1-associated condition. In another aspect, thesolid state form is the Amorphous Freebase. In another aspect, the solidstate form is the Freebase Hydrate Form B. In another aspect, the solidstate form is the Freebase Hydrate Form C. In another aspect, the solidstate form is the Tartrate Hydrate. In another aspect, the solid stateform is the Freebase Anhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of immunomodulation,inflammation, and proliferative disorders (such as cancer) in a subject,wherein the method comprises administering to the subject, particularlya human subject suffering from or susceptible to the condition, atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of a conditionselected from the group consisting of immunomodulation, inflammation,and proliferative disorders (such as cancer) in a subject, particularlyin a human subject suffering from or susceptible to the condition, theuse comprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In one aspect, the solidstate form is the Amorphous Freebase. In another aspect, the solid stateform is the Freebase Anhydrate Form D. In another aspect, the solidstate form is the Freebase Hydrate Form B. In another aspect, the solidstate form is the Freebase Hydrate Form C. In another aspect, the solidstate form is the Tartrate Hydrate.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of rheumatoid arthritis,multiple sclerosis, experimental allergic encephalomyelitis, systemiclupus erythematosus. Crohn's disease, atopic dermatitis, vasculitis,cardiomyopathy, psoriasis, Reiter's syndrome, glomerulonephritis,ulcerative colitis, allergic asthma, insulin-dependent diabetes,peripheral neuropathy, uveitis, fibrosing alveolitis, type 1 diabetes,juvenile diabetes, juvenile arthritis, Castleman disease, neutropenia,endometriosis, autoimmune thyroid disease, sperm and testicularautoimmunity, scleroderma, axonal and neuronal neuropathies, allergicrhinitis. Sjogren's syndrome, hemolytic anemia, Graves' disease,Hashimoto's thyroiditis, IgA nephropathy, amyloidosis, ankylosingspondylitis, Behcet's disease, sarcoidosis, vesiculobullous dermatosis,myositis, primary biliary cirrhosis, polymyalgia rheumatica, autoimmuneimmunodeficiency, Chagas disease, Kawasaki syndrome, psoriaticarthritis, celiac sprue, myasthenia gravis, autoimmune myocarditis.POEMS syndrome, and chronic fatigue syndrome in a subject, wherein themethod comprises administering to the subject, particularly a humansubject suffering from or susceptible to the condition, atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of a conditionselected from the group consisting of rheumatoid arthritis, multiplesclerosis, experimental allergic encephalomyelitis, systemic lupuserythematosus, Crohn's disease, atopic dermatitis, vasculitis,cardiomyopathy, psoriasis, Reiter's syndrome, glomerulonephritis,ulcerative colitis, allergic asthma, insulin-dependent diabetes,peripheral neuropathy, uveitis, fibrosing alveolitis, type 1 diabetes,juvenile diabetes, juvenile arthritis, Castleman disease, neutropenia,endometriosis, autoimmune thyroid disease, sperm and testicularautoimmunity, scleroderma, axonal and neuronal neuropathies, allergicrhinitis, Sjogren's syndrome, hemolytic anemia, Graves' disease,Hashimoto's thyroiditis, IgA nephropathy, amyloidosis, ankylosingspondylitis, Behcet's disease, sarcoidosis, vesiculobullous dermatosis,myositis, primary biliary cirrhosis, polymyalgia rheumatica, autoimmuneimmunodeficiency, Chagas disease, Kawasaki syndrome, psoriaticarthritis, celiac sprue, myasthenia gravis, autoimmune myocarditis,POEMS syndrome, and chronic fatigue syndrome in a subject, particularlyin a human subject suffering from or susceptible to the condition, theuse comprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In one aspect, the solidstate form is the Amorphous Freebase. In another aspect, the solid stateform is the Freebase Hydrate Form B. In another aspect, the solid stateform is the Freebase Hydrate Form C. In another aspect, the solid stateform is the Tartrate Hydrate. In another aspect, the solid state form isthe Freebase Anhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of rheumatoid arthritis(including moderate to severe rheumatoid arthritis), systemic lupuserythematosus, multiple sclerosis, Crohn's disease (including moderateto severe Crohn's disease), psoriasis (including moderate to severechronic plaque psoriasis), ulcerative colitis (including moderate tosevere ulcerative colitis), ankylosing spondylitis, psoriatic arthritis,juvenile idiopathic arthritis (including moderate to severepolyarticular juvenile idiopathic arthritis), diabetic nephropathy, dryeye syndrome, Sjogren's syndrome, alopecia areata, vitiligo, and atopicdermatitis in a subject, wherein the method comprises administering tothe subject, particularly a human subject suffering from or susceptibleto the condition, a therapeutically effective amount of Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of a conditionselected from the group consisting of rheumatoid arthritis (includingmoderate to severe rheumatoid arthritis), systemic lupus erythematosus,multiple sclerosis, Crohn's disease (including moderate to severeCrohn's disease), psoriasis (including moderate to severe chronic plaquepsoriasis), ulcerative colitis (including moderate to severe ulcerativecolitis), ankylosing spondylitis, psoriatic arthritis, juvenileidiopathic arthritis (including moderate to severe polyarticularjuvenile idiopathic arthritis), diabetic nephropathy, dry eye syndrome,Sjogren's syndrome, alopecia areata, vitiligo, and atopic dermatitis ina subject, particularly in a human subject suffering from or susceptibleto the condition, the use comprising administering to the subject atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one aspect, the solid state form is the AmorphousFreebase. In another aspect, the solid state form is the FreebaseHydrate Form B. In another aspect, the solid state form is the FreebaseHydrate Form C. In another aspect, the solid state form is the TartrateHydrate. In another aspect, the solid state form is the FreebaseAnhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of an ocular condition,systemic inflammatory response syndrome, juvenile rheumatoid arthritis,systemic onset juvenile rheumatoid arthritis, type III hypersensitivityreactions, type IV hypersensitivity, inflammation of the aorta,iridocyclitis/uveitis/optic neuritis, juvenile spinal muscular atrophy,diabetic retinopathy or microangiopathy, chronic inflammation,ulcerative colitis, inflammatory bowel disease, allergic diseases,dermatitis scleroderma, acute or chronic immune disease associated withorgan transplantation, psoriatic arthropathy, ulcerative coliticarthropathy, autoimmune bullous disease, autoimmune hemolytic anemia,rheumatoid arthritis associated interstitial lung disease, systemiclupus erythematosus associated lung disease,dermatomyositis/polymyositis associated lung disease, Sjögren'ssyndrome/disease associated lung disease, ankylosing spondylitis andankylosing spondylitis-associated lung disease, autoimmune hepatitis,type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis),type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmunemediated hypoglycemia, psoriasis type 1, psoriasis type 2, plaquepsoriasis, moderate to severe chronic plaque psoriasis, autoimmuneneutropenia, sperm autoimmunity, multiple sclerosis (all subtypes),acute rheumatic fever, rheumatoid spondylitis, Sjögren's syndrome, andautoimmune thrombocytopenia in a subject, wherein the method comprisesadministering to the subject, particularly a human subject sufferingfrom or susceptible to the condition, a therapeutically effective amountof Compound 1 freebase or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1. In another aspect, the presentdisclosure relates to Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 for use intreatment of a condition selected from the group consisting of an ocularcondition, systemic inflammatory response syndrome, juvenile rheumatoidarthritis, systemic onset juvenile rheumatoid arthritis, type IIIhypersensitivity reactions, type IV hypersensitivity, inflammation ofthe aorta, iridocyclitis/uveitis/optic neuritis, juvenile spinalmuscular atrophy, diabetic retinopathy or microangiopathy, chronicinflammation, ulcerative colitis, inflammatory bowel disease, allergicdiseases, dermatitis scleroderma, acute or chronic immune diseaseassociated with organ transplantation, psoriatic arthropathy, ulcerativecolitic arthropathy, autoimmune bullous disease, autoimmune hemolyticanemia, rheumatoid arthritis associated interstitial lung disease,systemic lupus erythematosus associated lung disease,dermatomyositis/polymyositis associated lung disease, Sjögren'ssyndrome/disease associated lung disease, ankylosing spondylitis andankylosing spondylitis-associated lung disease, autoimmune hepatitis,type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis),type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmunemediated hypoglycemia, psoriasis type 1, psoriasis type 2, plaquepsoriasis, moderate to severe chronic plaque psoriasis, autoimmuneneutropenia, sperm autoimmunity, multiple sclerosis (all subtypes),acute rheumatic fever, rheumatoid spondylitis, Sjögren's syndrome, andautoimmune thrombocytopenia in a subject, particularly in a humansubject suffering from or susceptible to the condition, the usecomprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In one aspect, the solidstate form is the Amorphous Freebase. In another aspect, the solid stateform is the Freebase Hydrate Form B. In another aspect, the solid stateform is the Freebase Hydrate Form C. In another aspect, the solid stateform is the Tartrate Hydrate. In another aspect, the solid state form isthe Freebase Anhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of rheumatoid arthritis,juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis,psoriasis, plaque psoriasis, nail psoriasis, psoriatic arthritis,ankylosing spondylitis, alopecia areata, hidradenitis suppurativa,atopic dermatitis, and systemic lupus erythematosus in a subject,wherein the method comprises administering to the subject atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of a conditionselected from the group consisting of rheumatoid arthritis, juvenileidiopathic arthritis, Crohn's disease, ulcerative colitis, psoriasis,plaque psoriasis, nail psoriasis, psoriatic arthritis, ankylosingspondylitis, alopecia areata, hidradenitis suppurativa, atopicdermatitis, and systemic lupus erythematosus in a subject, particularlyin a human subject suffering from or susceptible to the condition, theuse comprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a solid state form of Compound 1. Inone aspect, the solid state form is the Amorphous Freebase. In anotheraspect, the solid state form is the Freebase Hydrate Form B. In anotheraspect, the solid state form is the Freebase Hydrate Form C. In anotheraspect, the solid state form is the Tartrate Hydrate. In another aspect,the solid state form is the Freebase Anhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatinga condition selected from the group consisting of rheumatoid arthritis.Crohn's disease, ankylosing spondylitis, psoriatic arthritis, psoriasis,ulcerative colitis, systemic lupus erythematosus, lupus nephritis,diabetic nephropathy, dry eye syndrome, Sjogren's syndrome, alopeciaareata, vitiligo, and atopic dermatitis in a subject, wherein the methodcomprises administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In another aspect, thepresent disclosure relates to Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 for use intreatment of a condition selected from the group consisting ofrheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriaticarthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus,lupus nephritis, diabetic nephropathy, dry eye syndrome, Sjogren'ssyndrome, alopecia areata, vitiligo, and atopic dermatitis in a subject,particularly in a human subject suffering from or susceptible to thecondition, the use comprising administering to the subject atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one aspect, the solid state form is the AmorphousFreebase. In another aspect, the solid state form is the FreebaseHydrate Form B. In another aspect, the solid state form is the FreebaseHydrate Form C. In another aspect, the solid state form is the TartrateHydrate. In another aspect, the solid state form is the FreebaseAnhydrate Form D.

In one embodiment, the present disclosure relates to methods of treatingarthritis in a subject, wherein the method comprises administering tothe subject a therapeutically effective amount of Compound 1 freebase ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of arthritis in asubject, particularly in a human subject suffering from or susceptibleto arthritis, the use comprising administering to the subject atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one aspect, the arthritis is selected from the groupconsisting of rheumatoid arthritis, juvenile idiopathic arthritis, andpsoriatic arthritis. In another aspect, the arthritis is rheumatoidarthritis. In another aspect, the arthritis is juvenile idiopathicarthritis. In another aspect, the arthritis is psoriatic arthritis. Inanother aspect, the solid state form is the Amorphous Freebase. Inanother aspect, the solid state form is the Freebase Hydrate Form B. Inanother aspect, the solid state form is the Freebase Hydrate Form C. Inanother aspect, the solid state form is the Tartrate Hydrate. In anotheraspect, the solid state form is the Freebase Anhydrate Form D. Inanother aspect, the solid state form is the Freebase Solvate Form A. Inanother aspect, the solid state form is the Hydrochloride Solvate formAA. In another aspect, the solid state form is the Hydrochloride SolvateForm BB. In another aspect, the solid state form is the HydrochlorideSolvate Form CC. In another aspect, the solid state form is theL-Maleate Form AAA. In another aspect, the solid state form is theL-Maleate Form BBB.

In one embodiment, the present disclosure relates to methods of treatinga spondyloarthropathy in a subject, wherein the method comprisesadministering to the subject a therapeutically effective amount ofCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1. In another aspect, the presentdisclosure relates to Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 for use intreatment of spondyloarthropathy, particularly in a human subjectsuffering from or susceptible to spondyloarthropathy, the use comprisingadministering to the subject a therapeutically effective amount ofCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1. In one aspect, the spondyloarthropathyis ankylosing spondylitis. In another aspect, the solid state form isthe Amorphous Freebase. In another aspect, the solid state form is theFreebase Hydrate Form B. In another aspect, the solid state form is theFreebase Hydrate Form C. In another aspect, the solid state form is theTartrate Hydrate. In another aspect, the solid state form is theFreebase Anhydrate Form D. In another aspect, the solid state form isthe Freebase Solvate Form A. In another aspect, the solid state form isthe Hydrochloride Solvate form AA. In another aspect, the solid stateform is the Hydrochloride Solvate Form BB. In another aspect, the solidstate form is the Hydrochloride Solvate Form CC. In another aspect, thesolid state form is the L-Maleate Form AAA. In another aspect, the solidstate form is the L-Maleate Form BBB.

In one embodiment, the present disclosure relates to methods of treatinga gastrointestinal condition in a subject, wherein the method comprisesadministering to the subject a therapeutically effective amount ofCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1. In another aspect, the presentdisclosure relates to Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 for use intreatment of a gastrointestinal condition, particularly in a humansubject suffering from or susceptible to a gastrointestinal condition,the use comprising administering to the subject a therapeuticallyeffective amount of Compound 1 freebase or a pharmaceutically acceptablesalt thereof or a solid state form of Compound 1. In one aspect, thegastrointestinal condition is selected from the group consisting ofCrohn's disease and ulcerative colitis. In another aspect, thegastrointestinal condition is Crohn's disease. In another aspect, thegastrointestinal condition is ulcerative colitis. In another aspect, thesolid state form is the Amorphous Freebase. In another aspect, the solidstate form is the Freebase Hydrate Form B. In another aspect, the solidstate form is the Freebase Hydrate Form C. In another aspect, the solidstate form is the Tartrate Hydrate. In another aspect, the solid stateform is the Freebase Anhydrate Form D. In another aspect, the solidstate form is the Freebase Solvate Form A. In another aspect, the solidstate form is the Hydrochloride Solvate form AA. In another aspect, thesolid state form is the Hydrochloride Solvate Form BB. In anotheraspect, the solid state form is the Hydrochloride Solvate Form CC. Inanother aspect, the solid state form is the L-Maleate Form AAA. Inanother aspect, the solid state form is the L-Maleate Form BBB.

In one embodiment, the present disclosure relates to methods of treatinga skin condition, wherein the method comprises administering to thesubject a therapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In another aspect, the present disclosure relates toCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 for use in treatment of a skin condition,particularly in a human subject suffering from or susceptible to a skincondition, the use comprising administering to the subject atherapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one aspect, the skin condition is selected from the groupconsisting of psoriasis, plaque psoriasis, nail psoriasis, andhidradenitis suppurativa. In another aspect, the skin condition ispsoriasis. In another aspect, the skin condition is plaque psoriasis. Inanother aspect, the skin condition is nail psoriasis. In another aspect,the skin condition is hidradenitis suppurativa. In another aspect, theskin condition is atopic dermatitis. In another aspect, the solid stateform is the Amorphous Freebase. In another aspect, the solid state formis the Freebase Hydrate Form B. In another aspect, the solid state formis the Freebase Hydrate Form C. In another aspect, the solid state formis the Tartrate Hydrate. In another aspect, the solid state form is theFreebase Anhydrate Form D. In another aspect, the solid state form isthe Freebase Solvate Form A. In another aspect, the solid state form isthe Hydrochloride Solvate form AA. In another aspect, the solid stateform is the Hydrochloride Solvate Form BB. In another aspect, the solidstate form is the Hydrochloride Solvate Form CC. In another aspect, thesolid state form is the L-Maleate Form AAA. In another aspect, the solidstate form is the L-Maleate Form BBB.

The therapeutically effective dose level for any particular subject willdepend upon the specific situation and can depend upon a variety offactors including the type, age, weight, sex, diet, and condition of thesubject being treated; the severity of the pathological condition;activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thesubject; the route of administration; the duration of the treatment;pharmacological considerations, such as the activity, efficacy,pharmacokinetic, and toxicology profiles of the particular compound orsalt used; whether a drug delivery system is utilized; drugs used incombination or coincidental with the specific compound employed; andlike factors well-known in the medical arts. An ordinarily skilledphysician provided with the disclosure of the present application willbe able to determine appropriate dosages and regimens for administrationof the therapeutic agent to the subject, and to adjust such dosages andregimens as necessary during the course of treatment, in accordance withmethods well-known in the therapeutic arts. It is well within the skillof the art to start doses of the compound at levels lower than requiredto achieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved. Thus, the dosage regimenactually employed can vary widely, and therefore, can derive from thepreferred dosage regimen set forth below.

The total daily dose of the solid state form (administered in single ordivided doses) typically is from about 0.001 to about 100 mg/kg, or fromabout 0.001 to about 30 mg/kg, or from about 0.001 to about 15 mg/kg. Inanother embodiment, the total daily dose is from about 0.01 to about 10mg/kg (i.e., mg of the compound or salt per kg body weight). Dosage unitcompositions can contain such amounts or submultiples thereof to make upthe daily dose. In many instances, the administration of the compound orsalt will be repeated a plurality of times. Multiple doses per daytypically may be used to increase the total daily dose, if desired.

In one embodiment, the daily dose of the solid state form administeredto the subject is from about 0.01 mg to about 3000 mg. In one aspect,the daily dose is from about 0.1 mg to about 1000 mg. In another aspect,the daily dose is from is from about 1 mg to about 500 mg. In anotheraspect, the daily dose is from about 1 mg to about 250 mg. In anotheraspect, the daily dose is from about 1 mg to about 100 mg. In anotheraspect, the daily dose is from about 1 mg to about 50 mg. In anotheraspect, the daily dose is from about 1 mg to about 45 mg. In anotheraspect, the daily dose is from about 1 mg to about 30 mg. In anotheraspect, the daily dose is from about 1 mg to about 25 mg. In anotheraspect, the daily dose is from about 1 mg to about 24 mg. In anotheraspect, the daily dose is from about 1 mg to about 15 mg. In anotheraspect, the daily dose is from about 1 mg to about 7.5 mg. In anotheraspect, the daily dose is from about 25 mg to about 50 mg. In anotheraspect, the daily dose is from about 1 mg to about 10 mg. In anotheraspect, the daily dose is from about 10 mg to about 20 mg. In anotheraspect, the daily dose is from about 20 mg to about 30 mg. In anotheraspect, the daily dose is from about 30 mg to about 40 mg. In anotheraspect, the daily dose is from about 7.5 mg to about 45 mg. In anotheraspect, the daily dose is from about 15 mg to about 30 mg. In anotheraspect, the daily dose is about 3 mg. In another aspect, the daily doseis about 6 mg. In another aspect, the daily dose is about 7.5 mg. Inanother aspect, the daily dose is about 12 mg. In another aspect, thedaily dose is about 15 mg. In another aspect, the daily dose is about 18mg. In another aspect, the daily dose is about 24 mg. In another aspect,the daily dose is about 30 mg. In another aspect, the daily dose isabout 36 mg. In another aspect, the daily dose is about 45 mg.

In one embodiment, a dose of about 3 mg, about 6 mg, about 12 mg, orabout 24 mg per unit dosage form (e.g., per tablet or capsule) of asolid state form of Compound 1 is administered orally BID (twice daily)in equal amounts (e.g., twice a day, about 3 mg each time) to a humansubject.

In one embodiment, the disclosure relates to a method of treating asubject having rheumatoid arthritis, the method comprising administeringto the subject about 3 mg, per unit dosage form (e.g., per tablet orcapsule) of a solid state form of Compound 1 orally BID (twice daily) inequal amounts (e.g., twice a day, about 3 mg each time). In anotheraspect, the present disclosure relates a solid state form of Compound 1for use in treating rheumatoid arthritis in a subject, particularly in ahuman subject suffering from or susceptible to rheumatoid arthritis, theuse comprising administering to the subject about 3 mg, per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1orally BID (twice daily) in equal amounts (e.g., twice a day, about 3 mgeach time).

In one embodiment, the disclosure relates to a method of treating asubject having rheumatoid arthritis, the method comprising administeringto the subject about 6 mg, per unit dosage form (e.g., per tablet orcapsule) of a solid state form of Compound 1 orally BID (twice daily) inequal amounts (e.g., twice a day, about 6 mg each time). In anotheraspect, the present disclosure relates a solid state form of Compound 1for use in treating rheumatoid arthritis in a subject, particularly in ahuman subject suffering from or susceptible to rheumatoid arthritis, theuse comprising administering to the subject about 6 mg, per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1orally BID (twice daily) in equal amounts (e.g., twice a day, about 6 mgeach time).

In one embodiment, the disclosure relates to a method of treating asubject having rheumatoid arthritis, the method comprising administeringto the subject about 12 mg, per unit dosage form (e.g., per tablet orcapsule) of a solid state form of Compound 1 orally BID (twice daily) inequal amounts (e.g., twice a day, about 12 mg each time). In anotheraspect, the present disclosure relates a solid state form of Compound 1for use in treating rheumatoid arthritis in a subject, particularly in ahuman subject suffering from or susceptible to rheumatoid arthritis, theuse comprising administering to the subject about 12 mg, per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1orally BID (twice daily) in equal amounts (e.g., twice a day, about 12mg each time).

In one embodiment, the disclosure relates to a method of treating asubject having rheumatoid arthritis, the method comprising administeringto the subject about 24 mg, per unit dosage form (e.g., per tablet orcapsule) of a solid state form of Compound 1 orally BID (twice daily) inequal amounts (e.g., twice a day, about 24 mg each time). In anotheraspect, the present disclosure relates a solid state form of Compound 1for use in treating rheumatoid arthritis in a subject, particularly in ahuman subject suffering from or susceptible to rheumatoid arthritis, theuse comprising administering to the subject about 24 mg, per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1orally BID (twice daily) in equal amounts (e.g., twice a day, about 24mg each time).

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 7.5 mg per unitdosage form (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 7.5 mg per unitdosage form (e.g., per tablet or capsule) of a solid state form ofCompound 1. In one embodiment, the methods or uses compriseadministering orally QD (once daily) to a human subject a solid stateform of Compound 1 in an amount sufficient to deliver 7.5 mg per unitdosage form (e.g., per tablet or capsule) of Compound 1 freebaseequivalent to the subject. In one embodiment, the solid state form isthe Amorphous Freebase. In one embodiment, the solid state form is theFreebase Hydrate Form B. In one embodiment, the solid state form is theFreebase Hydrate Form C. In one embodiment, the solid state form is theTartrate Hydrate. In another aspect, the solid state form is theFreebase Anhydrate Form D.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 15 mg per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 15 mg per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1.In one embodiment, the methods or uses comprise administering orally QD(once daily) to a human subject a solid state form of Compound 1 in anamount sufficient to deliver 15 mg per unit dosage form (e.g., pertablet or capsule) of Compound 1 freebase equivalent to the subject. Inone embodiment, the solid state form is the Amorphous Freebase. In oneembodiment, the solid state form is the Freebase Hydrate Form B. In oneembodiment, the solid state form is the Freebase Hydrate Form C. In oneembodiment, the solid state form is the Tartrate Hydrate. In anotheraspect, the solid state form is the Freebase Anhydrate Form D.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 24 mg of Compound 1freebase or a pharmaceutically acceptable salt thereof. The 24 mg QDdose of Compound 1 freebase or a pharmaceutically acceptable saltthereof may be administered as either a single dosage form comprisingabout 24 mg per unit dosage form (e.g., per tablet or capsule) ofCompound 1 freebase or a pharmaceutically acceptable salt thereof, ortwo dosage forms comprising about 12 mg per unit dosage form (e.g., pertablet or capsule) of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof administered simultaneously.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 24 mg of a solidstate form of Compound 1. In one embodiment, the methods or usescomprise administering orally QD (once daily) to a human subject a solidstate form of Compound 1 in an amount sufficient to deliver 24 mg ofCompound 1 freebase equivalent to the subject. The 24 mg QD dose of thesolid state form of Compound 1 may be administered as either a singledosage form comprising about 24 mg per unit dosage form (e.g., pertablet or capsule) of the solid state form of Compound 1, or two dosageforms comprising about 12 mg per unit dosage form (e.g., per tablet orcapsule) of the solid state form of Compound 1 administeredsimultaneously. In one embodiment, the solid state form is the AmorphousFreebase. In one embodiment, the solid state form is the FreebaseHydrate Form B. In one embodiment, the solid state form is the FreebaseHydrate Form C. In one embodiment, the solid state form is the TartrateHydrate. In another aspect, the solid state form is the FreebaseAnhydrate Form D.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 30 mg per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 30 mg per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1.In one embodiment, the methods or uses comprise administering orally QD(once daily) to a human subject a solid state form of Compound 1 in anamount sufficient to deliver 30 mg per unit dosage form (e.g., pertablet or capsule) of Compound 1 freebase equivalent to the subject. Inone embodiment, the solid state form is the Amorphous Freebase. In oneembodiment, the solid state form is the Freebase Hydrate Form B. In oneembodiment, the solid state form is the Freebase Hydrate Form C. In oneembodiment, the solid state form is the Tartrate Hydrate. In anotheraspect, the solid state form is the Freebase Anhydrate Form D.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 36 mg per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 36 mg per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1.In one embodiment, the methods or uses comprise administering orally QD(once daily) to a human subject a solid state form of Compound 1 in anamount sufficient to deliver 36 mg per unit dosage form (e.g., pertablet or capsule) of Compound 1 freebase equivalent to the subject. Inone embodiment, the solid state form is the Amorphous Freebase. In oneembodiment, the solid state form is the Freebase Hydrate Form B. In oneembodiment, the solid state form is the Freebase Hydrate Form C. In oneembodiment, the solid state form is the Tartrate Hydrate. In anotheraspect, the solid state form is the Freebase Anhydrate Form D.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 45 mg per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof.

In another embodiment, the methods or uses comprise administering orallyQD (once daily) to a human subject a dose of about 45 mg per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1.In one embodiment, the methods or uses comprise administering orally QD(once daily) to a human subject a solid state form of Compound 1 in anamount sufficient to deliver 45 mg per unit dosage form (e.g., pertablet or capsule) of Compound 1 freebase equivalent to the subject. Inone embodiment, the solid state form is the Amorphous Freebase. In oneembodiment, the solid state form is the Freebase Hydrate Form B. In oneembodiment, the solid state form is the Freebase Hydrate Form C. In oneembodiment, the solid state form is the Tartrate Hydrate. In anotheraspect, the solid state form is the Freebase Anhydrate Form D.

In certain embodiments, Compound 1 freebase or a pharmaceuticallyacceptable salt thereof and/or solid state forms thereof can be used totreat rheumatoid arthritis (RA), including reducing signs and symptomsof RA, inducing a major clinical response, inhibiting the progression ofor treating structural damage associated with RA, and improving physicalfunction in adult subjects, such as adult subjects with moderately toseverely active RA. In one embodiment, Compound 1 freebase or apharmaceutically acceptable salt thereof and/or solid state formsthereof are used to treat RA in adult subjects. In one embodiment,Compound 1 freebase or a pharmaceutically acceptable salt thereof and/orsolid state forms thereof are used to reduce signs and symptoms of RA inadult subjects. In one embodiment, Compound 1 freebase or apharmaceutically acceptable salt thereof and/or solid state formsthereof induce a major clinical response in adult subjects with RA. Inone embodiment. Compound 1 freebase or a pharmaceutically acceptablesalt thereof and/or solid state forms thereof are used to inhibit theprogression of structural damage associated with RA in adult subjects.In one embodiment, Compound 1 freebase and/or solid state forms thereofare used to treat structural damage associated with RA in adultsubjects. In one embodiment, Compound 1 freebase or a pharmaceuticallyacceptable salt thereof and/or solid state forms thereof are used toimprove physical function in adult subjects. In one embodiment, theadult subjects have RA. In another embodiment, the adult subjects havemoderately to severely active RA.

Compound 1 freebase or a pharmaceutically acceptable salt thereof orsolid state forms thereof may be used alone, or in combination withmethotrexate or other non-biologic disease-modifying anti-rheumaticdrugs (DMARDs), and/or in combination with anti-TNFα biological agents,such as TNF antagonists like chimeric, humanized or human TNFantibodies, adalimumab (such as HUMIRA™ brand adalimumab), infliximabsuch as CA2 (REMICADE™ brand infliximab), golimumab such as SIMPONI™(golimumab), certolizumab pegol such as CIMZIA™ tocilizumab such asACTEMRA™, CDP 571, and soluble p55 or p75 TNF receptors, derivatives,thereof, etanercept such as p75TNFR1gG (ENBREL™ brand etanercept) orp55TNFR1gG (lenercept).

Patients having active rheumatoid arthritis (RA) may be diagnosedaccording to 1987-revised American College of Rheumatology (ACR)classification criteria or the 2010 ACR/EULAR criteria. In certainembodiments, RA may be diagnosed based on patients having at least 6swollen and 6 tender joints. In certain embodiments, patients treatablewith Compound 1 or solid state forms thereof may include those who havefailed therapy with at least one (e.g., at least one but no more thanfour) DMARDs and/or have inadequate response to methotrexate,adalimumab, infliximab, etanercept, or other anti-TNFα biologicalagents, or non-anti-TNF biologics.

In certain embodiments, Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or solid state forms thereof halt diseaseprogression, and/or relieves at least a symptom of the disease, whichmay be detected or monitored by X-ray results, including radiographicprogression of joint damage.

In certain embodiments, therapeutic efficacy can be measured byimprovements in ACR20, ACR50, and/or ACR70, either in individualpatients or a population of patients in need of treatment. In certainembodiments, statistically significant improvement (as compared placeboor untreated control) over a treatment period (e.g., 1 week, 2 weeks, 4weeks, 6 weeks, 8 weeks, 12 weeks, 2 months, 3 months, 6 months, 1 year,2 years, 5 years, 10 years or more) in one or more of the ACR criteriais achieved. Statistical significance is manifested by a p value of lessthan 0.05, or less than 0.01.

Components of the ACR responses are well known in the art, and mayinclude the median number of tender joints, the median number of swollenjoints, physician global assessment such as one measured by visualanalog scale (VAS), patient global assessment such as one measured byvisual analog scale, pain such as one measured by visual analog scale,disability index of the Health Assessment Questionnaire (HAQ-DI score),and C-reactive protein (CRP) (mg/dL).

In certain embodiments, an ACR20 response is determined based on a 20%or greater improvement in tender joint count (TJC) and swollen jointcount (SJC) and greater than or equal to 3 of the 5 measures ofPatient's Assessment of Pain (VAS), Patient's Global Assessment ofDisease Activity (VAS), Physician's Global Assessment of DiseaseActivity (VAS), HAQ-DI, or high sensitivity C-reactive protein (hsCRP).In some embodiments, an ACR50 response is determined based on a 50% orgreater improvement in TJC and SJC and greater than or equal to 3 of the5 measures of Patient's Assessment of Pain (VAS), Patient's GlobalAssessment of Disease Activity (VAS), Physician's Global Assessment ofDisease Activity (VAS), HAQ-DI, or hsCRP. An ACR70 response isdetermined based on a 70% or greater improvement in TJC and SJC andgreater than or equal to 3 of the 5 measures of Patient's Assessment ofPain (VAS). Patient's Global Assessment of Disease Activity (VAS),Physician's Global Assessment of Disease Activity (VAS), HAQ-DI, orhsCRP. In certain embodiments, the ACR20, ACR50, or ACR70 responseoccurs by week 12 of treatment.

In certain embodiments, a DAS28 (disease activity score based on the 28joints examined) score is determined as a composite score derived fromfour of the following measures: examination of joints for swelling andtenderness, global scores of pain and overall status, blood markers ofinflammation (e.g. ESR (erythrocyte sedimentation rate) and CRP (Creactive protein), referred to herein as DAS28(CRP)), questionnaires(e.g. the HAQ (health assessment questionnaire) which assess function)and X-rays and other imaging techniques such as ultrasound and MRI.

In certain embodiments, structural joint damage can be assessedradiographically and expressed as change in Total Sharp Score (TSS) andits components, the erosion score and Joint Space Narrowing (JSN) score,for example, at week 12 compared to baseline, or at week 24 as comparedto baseline.

In certain embodiments, improvement in signs and symptoms of the diseasecan be measured by patient physical function response, such asdisability index of Health Assessment Questionnaire (HAQ-DI), and/or thehealth-outcomes as assessed by The Short Form Health Survey (SF 36). Inone embodiment, improvement in signs and symptoms of the disease ismeasured by HAQ-DI, including the minimal clinically importantdifference (MCID) of −0.22. Improvement can also be measured by one orboth of Physical Component Summary (PCS) and the Mental ComponentSummary (MCS). Improvements can further be measured by Work InstabilityScale for RA (RA-WIS) (see Gilworth et al., Arthritis & Rheumatism(Arthritis Care & Research) 49(3): 349-354, 2003, incorporated byreference).

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 7.5 mg, per unit dosage form(e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). Inanother aspect, the present disclosure relates to Compound 1 freebase ora pharmaceutically acceptable salt thereof for use in treatment ofrheumatoid arthritis in a subject, particularly in a human subjectsuffering from or susceptible to rheumatoid arthritis, the usecomprising administering to the subject about 7.5 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). In oneembodiment, the subject has moderately to severely active rheumatoidarthritis. In one embodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 7.5 mg, per unit dosage form(e.g., per tablet or capsule) of a solid state form of Compound 1 orallyQD (once daily). In one embodiment, the method comprising administeringto the subject a solid state form of Compound 1 orally QD (once daily)in an amount sufficient to deliver 7.5 mg, per unit dosage form (e.g.,per tablet or capsule) of Compound 1 freebase equivalent to the subject.In another aspect, the present disclosure relates to a solid state formof Compound 1 for use in treatment of rheumatoid arthritis in a subject,particularly in a human subject suffering from or susceptible torheumatoid arthritis, the use comprising administering to the subjectabout 7.5 mg, per unit dosage form (e.g., per tablet or capsule) of asolid state form of Compound 1 orally QD (once daily). In oneembodiment, the solid state form delivers about 7.5 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase equivalent tothe subject. In one embodiment, the solid state form is the FreebaseHydrate Form B. In one embodiment, the solid state form is the FreebaseHydrate Form C. In one embodiment, the solid state form is the TartrateHydrate. In one embodiment, the solid state form is Freebase AnhydrateForm D. In one embodiment, the subject has moderately to severely activerheumatoid arthritis. In another aspect, the solid state form is theFreebase Solvate Form A. In another aspect, the solid state form is theHydrochloride Solvate form AA. In another aspect, the solid state formis the Hydrochloride Solvate Form BB. In another aspect, the solid stateform is the Hydrochloride Solvate Form CC. In another aspect, the solidstate form is the L-Maleate Form AAA. In another aspect, the solid stateform is the L-Maleate Form BBB. In one embodiment, the subject is anadult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 15 mg, per unit dosage form(e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). Inanother aspect, the present disclosure relates to Compound 1 freebase ora pharmaceutically acceptable salt thereof for use in treatment ofrheumatoid arthritis in a subject, particularly in a human subjectsuffering from or susceptible to rheumatoid arthritis, the usecomprising administering to the subject about 15 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). In oneembodiment, the subject has moderately to severely active rheumatoidarthritis. In one embodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 15 mg, per unit dosage form(e.g., per tablet or capsule) of a solid state form of Compound 1 orallyQD (once daily). In one embodiment, the method comprising administeringto the subject a solid state form of Compound 1 orally QD (once daily)in an amount sufficient to deliver 15 mg, per unit dosage form (e.g.,per tablet or capsule) of Compound 1 freebase equivalent to the subject.In another aspect, the present disclosure relates to a solid state formof Compound 1 for use in treatment of rheumatoid arthritis in a subject,particularly in a human subject suffering from or susceptible torheumatoid arthritis, the use comprising administering to the subjectabout 15 mg, per unit dosage form (e.g., per tablet or capsule) of asolid state form of Compound 1 orally QD (once daily). In oneembodiment, the solid state form delivers about 15 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase equivalent tothe subject. In one embodiment, the solid state form is the FreebaseHydrate Form B. In one embodiment, the solid state form is the FreebaseHydrate Form C. In one embodiment, the solid state form is the TartrateHydrate. In one embodiment, the solid state form is Freebase AnhydrateForm D. In one embodiment, the subject has moderately to severely activerheumatoid arthritis. In another aspect, the solid state form is theFreebase Solvate Form A. In another aspect, the solid state form is theHydrochloride Solvate form AA. In another aspect, the solid state formis the Hydrochloride Solvate Form BB. In another aspect, the solid stateform is the Hydrochloride Solvate Form CC. In another aspect, the solidstate form is the L-Maleate Form AAA. In another aspect, the solid stateform is the L-Maleate Form BBB. In one embodiment, the subject is anadult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 24 mg of Compound 1 freebaseor a pharmaceutically acceptable salt thereof orally QD (once daily). Inanother aspect, the present disclosure relates to Compound 1 freebase ora pharmaceutically acceptable salt thereof for use in treatment ofrheumatoid arthritis in a subject, particularly in a human subjectsuffering from or susceptible to rheumatoid arthritis, the usecomprising administering to the subject about 24 mg of Compound 1freebase or a pharmaceutically acceptable salt thereof orally QD (oncedaily). The 24 mg dose of Compound 1 freebase or a pharmaceuticallyacceptable salt thereof may be administered as either a single dosageform comprising about 24 mg per unit dosage form (e.g., per tablet orcapsule) of Compound 1 freebase or a pharmaceutically acceptable saltthereof, or two dosage forms comprising about 12 mg per unit dosage form(e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof administered simultaneously. Inone embodiment, the subject has moderately to severely active rheumatoidarthritis. In one embodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 24 mg of a solid state formof Compound 1 orally QD (once daily). In one embodiment, the methodcomprising administering to the subject a solid state form of Compound 1orally QD (once daily) in an amount sufficient to deliver 24 mg ofCompound 1 freebase equivalent to the subject. In another aspect, thepresent disclosure relates to a solid state form of Compound 1 for usein treatment of rheumatoid arthritis in a subject, particularly in ahuman subject suffering from or susceptible to rheumatoid arthritis, theuse comprising administering to the subject about 24 mg of a solid stateform of Compound 1 orally QD (once daily). In one embodiment, the solidstate form delivers about 24 mg of Compound 1 freebase equivalent to thesubject. The 24 mg dose of the solid state form of Compound 1 may beadministered as either a single dosage form comprising about 24 mg perunit dosage form (e.g., per tablet or capsule) of the solid state formof Compound 1, or two dosage forms comprising about 12 mg per unitdosage form (e.g., per tablet or capsule) of the solid state form ofCompound 1 administered simultaneously. In one embodiment, the solidstate form is the Freebase Hydrate Form B. In one embodiment, the solidstate form is the Freebase Hydrate Form C. In one embodiment, the solidstate form is the Tartrate Hydrate. In one embodiment, the solid stateform is the Freebase Anhydrate Form D. In another aspect, the solidstate form is the Freebase Solvate Form A. In another aspect, the solidstate form is the Hydrochloride Solvate form AA. In another aspect, thesolid state form is the Hydrochloride Solvate Form BB. In anotheraspect, the solid state form is the Hydrochloride Solvate Form CC. Inanother aspect, the solid state form is the L-Maleate Form AAA. Inanother aspect, the solid state form is the L-Maleate Form BBB. In oneembodiment, the subject has moderately to severely active rheumatoidarthritis. In one embodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 30 mg, per unit dosage form(e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). Inanother aspect, the present disclosure relates to Compound 1 freebase ora pharmaceutically acceptable salt thereof for use in treatment ofrheumatoid arthritis in a subject, particularly in a human subjectsuffering from or susceptible to rheumatoid arthritis, the usecomprising administering to the subject about 30 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). In oneembodiment, the subject has moderately to severely active rheumatoidarthritis. In one embodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 30 mg, per unit dosage form(e.g., per tablet or capsule) of a solid state form of Compound 1 orallyQD (once daily). In one embodiment, the method comprising administeringto the subject a solid state form of Compound 1 orally QD (once daily)in an amount sufficient to deliver 30 mg, per unit dosage form (e.g.,per tablet or capsule) of Compound 1 freebase equivalent to the subject.In another aspect, the present disclosure relates to a solid state formof Compound 1 for use in treatment of rheumatoid arthritis in a subject,particularly in a human subject suffering from or susceptible torheumatoid arthritis, the use comprising administering to the subjectabout 30 mg, per unit dosage form (e.g., per tablet or capsule) of asolid state form of Compound 1 orally QD (once daily). In oneembodiment, the solid state form delivers about 30 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase equivalent tothe subject. In one embodiment, the solid state form is the FreebaseHydrate Form B. In one embodiment, the solid state form is the FreebaseHydrate Form C. In one embodiment, the solid state form is the TartrateHydrate. In one embodiment, the solid state form is the FreebaseAnhydrate Form D. In one embodiment, the subject has moderately toseverely active rheumatoid arthritis. In another aspect, the solid stateform is the Freebase Solvate Form A. In another aspect, the solid stateform is the Hydrochloride Solvate form AA. In another aspect, the solidstate form is the Hydrochloride Solvate Form BB. In another aspect, thesolid state form is the Hydrochloride Solvate Form CC. In anotheraspect, the solid state form is the L-Maleate Form AAA. In anotheraspect, the solid state form is the L-Maleate Form BBB. In oneembodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 36 mg, per unit dosage form(e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). Inanother aspect, the present disclosure relates to Compound 1 freebase ora pharmaceutically acceptable salt thereof for use in treatment ofrheumatoid arthritis in a subject, particularly in a human subjectsuffering from or susceptible to rheumatoid arthritis, the usecomprising administering to the subject about 36 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). In oneembodiment, the subject has moderately to severely active rheumatoidarthritis. In one embodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 36 mg, per unit dosage form(e.g., per tablet or capsule) of a solid state form of Compound 1 orallyQD (once daily). In one embodiment, the method comprising administeringto the subject a solid state form of Compound 1 orally QD (once daily)in an amount sufficient to deliver 36 mg, per unit dosage form (e.g.,per tablet or capsule) of Compound 1 freebase equivalent to the subject.In another aspect, the present disclosure relates to a solid state formof Compound 1 for use in treatment of rheumatoid arthritis in a subject,particularly in a human subject suffering from or susceptible torheumatoid arthritis, the use comprising administering to the subjectabout 36 mg, per unit dosage form (e.g., per tablet or capsule) of asolid state form of Compound 1 orally QD (once daily). In oneembodiment, the solid state form delivers about 36 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase equivalent tothe subject. In one embodiment, the solid state form is the FreebaseHydrate Form B. In one embodiment, the solid state form is the FreebaseHydrate Form C. In one embodiment, the solid state form is the TartrateHydrate. In one embodiment, the solid state form is the FreebaseAnhydrate Form D. In one embodiment, the subject has moderately toseverely active rheumatoid arthritis. In another aspect, the solid stateform is the Freebase Solvate Form A. In another aspect, the solid stateform is the Hydrochloride Solvate form AA. In another aspect, the solidstate form is the Hydrochloride Solvate Form BB. In another aspect, thesolid state form is the Hydrochloride Solvate Form CC. In anotheraspect, the solid state form is the L-Maleate Form AAA. In anotheraspect, the solid state form is the L-Maleate Form BBB. In oneembodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 45 mg, per unit dosage form(e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). Inanother aspect, the present disclosure relates to Compound 1 freebase ora pharmaceutically acceptable salt thereof for use in treatment ofrheumatoid arthritis in a subject, particularly in a human subjectsuffering from or susceptible to rheumatoid arthritis, the usecomprising administering to the subject about 45 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof orally QD (once daily). In oneembodiment, the subject has moderately to severely active rheumatoidarthritis. In one embodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingrheumatoid arthritis in a subject, the method comprising administeringto the subject, particularly a human subject suffering from orsusceptible to rheumatoid arthritis, about 45 mg, per unit dosage form(e.g., per tablet or capsule) of a solid state form of Compound 1 orallyQD (once daily). In one embodiment, the method comprising administeringto the subject a solid state form of Compound 1 orally QD (once daily)in an amount sufficient to deliver 45 mg, per unit dosage form (e.g.,per tablet or capsule) of Compound 1 freebase equivalent to the subject.In another aspect, the present disclosure relates to a solid state formof Compound 1 for use in treatment of rheumatoid arthritis in a subject,particularly in a human subject suffering from or susceptible torheumatoid arthritis, the use comprising administering to the subjectabout 45 mg, per unit dosage form (e.g., per tablet or capsule) of asolid state form of Compound 1 orally QD (once daily). In oneembodiment, the solid state form delivers about 45 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase equivalent tothe subject. In one embodiment, the solid state form is the FreebaseHydrate Form B. In one embodiment, the solid state form is the FreebaseHydrate Form C. In one embodiment, the solid state form is the TartrateHydrate. In one embodiment, the solid state form is the FreebaseAnhydrate Form D. In one embodiment, the subject has moderately toseverely active rheumatoid arthritis. In another aspect, the solid stateform is the Freebase Solvate Form A. In another aspect, the solid stateform is the Hydrochloride Solvate form AA. In another aspect, the solidstate form is the Hydrochloride Solvate Form BB. In another aspect, thesolid state form is the Hydrochloride Solvate Form CC. In anotheraspect, the solid state form is the L-Maleate Form AAA. In anotheraspect, the solid state form is the L-Maleate Form BBB. In oneembodiment, the subject is an adult.

In one embodiment, the disclosure relates to a method of treatingmoderate to severely active rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tomoderate to severely active rheumatoid arthritis, the method comprisingadministering to the subject a therapeutically effective amount ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1. In one embodiment, the methodcomprises administering to the subject about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule) of Compound 1 (freebase), or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1 in an amount sufficient todeliver to the subject about 7.5 mg or about 15 mg or about 30 mg orabout 45 mg, per unit dosage form (e.g., per tablet or capsule) ofCompound 1 freebase equivalent. In one embodiment, the method comprisesadministering to the subject about 7.5 mg or about 15 mg or about 30 mgor about 45 mg, per unit dosage form (e.g., per tablet or capsule) ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1. In one embodiment, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or the solidstate form of Compound 1 is administered to the subject orally QD (oncedaily). In another aspect, the disclosure relates to Compound 1 freebaseor a pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 (e.g., a crystalline hydrate or crystalline anhydrate), asdescribed in the present disclosure, for use in treatment of moderate toseverely active rheumatoid arthritis in an adult subject, particularlyin a human subject suffering from or susceptible to moderate to severelyactive rheumatoid arthritis, the use comprising administering to thesubject a therapeutically effective amount of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one embodiment, the solid state form is a crystallinehydrate. In one embodiment, the crystalline hydrate is the FreebaseHydrate Form B. In one embodiment, the crystalline hydrate is ahemihydrate. In one embodiment, the hemihydrate is Freebase Hydrate FormC. In one embodiment, the solid state form is a crystalline anhydrate.In one embodiment, the crystalline anhydrate is Freebase Anhydrate FormD. In one embodiment, the solid state form is the Freebase Solvate FormA. In another aspect, the solid state form is the Hydrochloride Solvateform AA. In one embodiment, the solid state form is the HydrochlorideSolvate Form BB. In one embodiment, the solid state form is theHydrochloride Solvate Form CC. In one embodiment, the solid state formis the L-Maleate Form AAA. In one embodiment, the solid state form isthe L-Maleate Form BBB. In one embodiment, the Compound 1 (freebase) ora pharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation. In oneembodiment, the formulation delivers about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg per unit dosage form (e.g., per tablet orcapsule) of Compound 1 (freebase equivalent) or a solid state form ofCompound 1 orally QD (once daily).

In one embodiment, the subject having moderate to severely activerheumatoid arthritis has, prior to treatment, at least one of thefollowing identifying characteristics: at least 6 swollen joints (basedon 66 joint counts), at least 6 tender joints (based on 68 jointcounts), high-sensitivity C-reactive protein (hsCRP) greater than theupper limit of normal (ULN), or positive test results for bothrheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP). Inone embodiment, the subject having moderate to severely activerheumatoid arthritis has, prior to treatment, at least 6 swollen joints(based on 66 joint counts) and at least 6 tender joints (based on 68joint counts). Methods for assessing tender and swollen joints areknown, and described in, for example, Scott, et al., Clinical andExperimental Rheumatology, 2014, Vol. 32 (Supp. 85), S7-S12.

Thus, in another embodiment, the present disclosure is directed to amethod of treating moderate to severely active rheumatoid arthritis inan adult subject, particularly in a human subject suffering from orsusceptible to moderate to severely active rheumatoid arthritis, themethod comprising administering to the subject a therapeuticallyeffective amount of Compound 1 (freebase), or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 (e.g., acrystalline hydrate or a crystalline anhydrate) as described herein,wherein the subject has symptoms selected from the group consisting ofat least 6 swollen joints, at least 6 tender joints, and combinationsthereof prior to treating. In one embodiment, the method comprisesadministering to the subject about 7.5 mg or about 15 mg or about 30 mgor about 45 mg, per unit dosage form (e.g., per tablet or capsule), perday of Compound 1 (freebase) or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1 in an amount sufficient todeliver to the subject about 7.5 or about 15 mg or about 30 mg or about45 mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent, wherein the subject has symptomsselected from the group consisting of at least 6 swollen joints, atleast 6 tender joints, and combinations thereof prior to treating. Inone embodiment, the method comprises administering to the subject about7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosageform (e.g., per tablet or capsule) of a solid state form of Compound 1.In another aspect, the disclosure relates to Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 (e.g., a crystalline hydrate or crystalline anhydrate), asdescribed in the present disclosure, for use in treatment of moderate toseverely active rheumatoid arthritis in an adult subject, particularlyin a human subject suffering from or susceptible to moderate to severelyactive rheumatoid arthritis, wherein the subject has symptoms selectedfrom the group consisting of at least 6 swollen joints, at least 6tender joints, and combinations thereof prior to treating, the usecomprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In one embodiment, thetherapeutically effective amount of the solid state form of Compound 1delivers to the subject about 7.5 mg or about 15 mg or about 30 mg orabout 45 mg per unit dosage form (e.g., per tablet or capsule) ofCompound 1 (freebase equivalent) or a solid state form of Compound 1orally QD (once daily). In one embodiment, the Compound 1 (freebase) ora pharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation. In oneembodiment, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the solid state form of Compound 1 is administered tothe subject orally QD (once daily). In one embodiment, the solid stateform is a crystalline hydrate. In one embodiment, the crystallinehydrate is the Freebase Hydrate Form B. In one embodiment, thecrystalline hydrate is the Freebase Hydrate Form C. In one embodiment,the solid state form is a crystalline anhydrate. In one embodiment, thecrystalline anhydrate is the Freebase Anhydrate Form D. In oneembodiment, the solid state form is Tartrate Hydrate. In one embodiment,the symptoms result from the progression of structural damage assessedby radiograph.

In one embodiment, the present disclosure is directed to a method oftreating moderate to severely active rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto moderate to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 7.5 mg, per unit dosageform (e.g., per tablet or capsule), per day of Compound 1 (freebase), ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 7.5mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent, wherein the subject has symptomsselected from the group consisting of at least 6 swollen joints, atleast 6 tender joints, and combinations thereof prior to treating. Inone embodiment, the method comprises administering to the subject about7.5 mg, per unit dosage form (e.g., per tablet or capsule), per day of asolid state form of Compound 1. In another aspect, the disclosurerelates to Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1 for use in treatment ofmoderate to severely active rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tomoderate to severely active rheumatoid arthritis, wherein the subjecthas symptoms selected from the group consisting of at least 6 swollenjoints, at least 6 tender joints, and combinations thereof prior totreating, the use comprising administering to the subject about 7.5 mg,per unit dosage form (e.g., per tablet or capsule) of Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1. In one embodiment, the solid state form is acrystalline hydrate. In one embodiment, the crystalline hydrate is theFreebase Hydrate Form B. In one embodiment, the crystalline hydrate isthe Freebase Hydrate Form C. In one embodiment, the solid state form isa crystalline anhydrate. In one embodiment, the crystalline anhydrate isthe Freebase Anhydrate Form D. In one embodiment, the solid state formis the Tartrate Hydrate. In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is administered orally QD (once daily). In one embodiment,the Compound 1 freebase or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the symptoms result from the progressionof structural damage assessed by radiograph.

In one embodiment, the present disclosure is directed to a method oftreating moderate to severely active rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto moderate to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 15 mg, per unit dosageform (e.g., per tablet or capsule), per day of Compound 1 (freebase), ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 15mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent, wherein the subject has symptomsselected from the group consisting of at least 6 swollen joints, atleast 6 tender joints, and combinations thereof prior to treating. Inone embodiment, the method comprises administering to the subject about15 mg, per unit dosage form (e.g., per tablet or capsule), per day of asolid state form of Compound 1. In another aspect, the disclosurerelates to Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1 for use in treatment ofmoderate to severely active rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tomoderate to severely active rheumatoid arthritis, wherein the subjecthas symptoms selected from the group consisting of at least 6 swollenjoints, at least 6 tender joints, and combinations thereof prior totreating, the use comprising administering to the subject about 15 mg,per unit dosage form (e.g., per tablet or capsule) of Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1. In one embodiment, the solid state form is acrystalline hydrate. In one embodiment, the crystalline hydrate is theFreebase Hydrate Form B. In one embodiment, the crystalline hydrate isthe Freebase Hydrate Form C. In one embodiment, the solid state form isa crystalline anhydrate. In one embodiment, the crystalline anhydrate isthe Freebase Anhydrate Form D. In one embodiment, the solid state formis the Tartrate Hydrate. In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is administered orally QD (once daily). In one embodiment,the Compound 1 freebase or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the symptoms result from the progressionof structural damage assessed by radiograph.

In one embodiment, the present disclosure is directed to a method oftreating moderate to severely active rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto moderate to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 30 mg, per unit dosageform (e.g., per tablet or capsule), per day of Compound 1 (freebase), ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 30mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent, wherein the subject has symptomsselected from the group consisting of at least 6 swollen joints, atleast 6 tender joints, and combinations thereof prior to treating. Inone embodiment, the method comprises administering to the subject about30 mg, per unit dosage form (e.g., per tablet or capsule), per day of asolid state form of Compound 1. In another aspect, the disclosurerelates to Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1 for use in treatment ofmoderate to severely active rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tomoderate to severely active rheumatoid arthritis, wherein the subjecthas symptoms selected from the group consisting of at least 6 swollenjoints, at least 6 tender joints, and combinations thereof prior totreating, the use comprising administering to the subject about 30 mg,per unit dosage form (e.g., per tablet or capsule) of Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1. In one embodiment, the solid state form is acrystalline hydrate. In one embodiment, the crystalline hydrate is theFreebase Hydrate Form B. In one embodiment, the crystalline hydrate isthe Freebase Hydrate Form C. In one embodiment, the solid state form isa crystalline anhydrate. In one embodiment, the crystalline anhydrate isthe Freebase Anhydrate Form D. In one embodiment, the solid state formis the Tartrate Hydrate. In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is administered orally QD (once daily). In one embodiment,the Compound 1 freebase or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the symptoms result from the progressionof structural damage assessed by radiograph.

In one embodiment, the present disclosure is directed to a method oftreating moderate to severely active rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto moderate to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 45 mg, per unit dosageform (e.g., per tablet or capsule), per day of Compound 1 (freebase), ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 45mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent, wherein the subject has symptomsselected from the group consisting of at least 6 swollen joints, atleast 6 tender joints, and combinations thereof prior to treating. Inone embodiment, the method comprises administering to the subject about45 mg, per unit dosage form (e.g., per tablet or capsule), per day of asolid state form of Compound 1. In another aspect, the disclosurerelates to Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1 for use in treatment ofmoderate to severely active rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tomoderate to severely active rheumatoid arthritis, wherein the subjecthas symptoms selected from the group consisting of at least 6 swollenjoints, at least 6 tender joints, and combinations thereof prior totreating, the use comprising administering to the subject about 45 mg,per unit dosage form (e.g., per tablet or capsule) of Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1. In one embodiment, the solid state form is acrystalline hydrate. In one embodiment, the crystalline hydrate is theFreebase Hydrate Form B. In one embodiment, the crystalline hydrate isthe Freebase Hydrate Form C. In one embodiment, the solid state form isa crystalline anhydrate. In one embodiment, the crystalline anhydrate isthe Freebase Anhydrate Form D. In one embodiment, the solid state formis the Tartrate Hydrate. In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is administered orally QD (once daily). In one embodiment,the Compound 1 freebase or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the symptoms result from the progressionof structural damage assessed by radiograph.

In one embodiment, the adult subject receiving the treatment achieves anACR20 response after treatment. In one embodiment, the adult subjectachieves an ACR20 response after treatment for at least twelve weeks(e.g., at week 12 of treating). In another embodiment, the adult subjectreceiving the treatment achieves an ACR50 response after treatment. Inone embodiment, the adult subject achieves an ACR50 response aftertreatment for at least twelve weeks (e.g., at week 12 of treating), orafter at least twenty-four weeks (e.g., at week 24). In anotherembodiment, the adult subject receiving the treatment achieves an ACR70response after treatment. In one embodiment, the adult subject achievesan ACR70 response after treatment for at least twelve weeks (e.g., atweek 12 of treating). In certain embodiments, the adult subject achievesan ACR20 response, an ACR50 response, and/or an ACR70 response followingtreatment for at least twelve weeks (e.g., at week 12 of treating).

In one embodiment, the adult subject receiving the treatment achieves anACR20 response after treatment for at least 8 weeks (e.g., at week 8 oftreating). In another embodiment, the adult subject receiving thetreatment achieves an ACR20 response after treatment for at least 6weeks (e.g., at week 6 of treating). In another embodiment, the adultsubject receiving the treatment achieves an ACR20 response aftertreatment for at least 4 weeks (e.g., at week 4 of treating). In anotherembodiment, the adult subject receiving the treatment achieves an ACR20response after treatment for at least 2 weeks (e.g., at week 2 oftreating).

In one embodiment, the adult subject receiving the treatment achieves anACR50 response after treatment for at least 8 weeks (e.g., at week 8 oftreating). In another embodiment, the adult subject receiving thetreatment achieves an ACR50 response after treatment for at least 6weeks (e.g., at week 6 of treating). In another embodiment, the adultsubject receiving the treatment achieves an ACR50 response aftertreatment for at least 4 weeks (e.g., at week 4 of treating). In anotherembodiment, the adult subject receiving the treatment achieves an ACR50response after treatment for at least 2 weeks (e.g., at week 2 oftreating).

In one embodiment, the adult subject receiving the treatment achieves anACR70 response after treatment for at least 8 weeks (e.g., at week 8 oftreating). In another embodiment, the adult subject receiving thetreatment achieves an ACR70 response after treatment for at least 6weeks (e.g., at week 6 of treating). In another embodiment, the adultsubject receiving the treatment achieves an ACR70 response aftertreatment for at least 4 weeks (e.g., at week 4 of treating).

In one embodiment, the adult subject receiving the treatment achieves achange in DAS28 score after treatment. In one embodiment, the change inDAS score is a decrease in DAS28(CRP) after treatment, as compared tobaseline (i.e., DAS28(CRP) prior to treatment). In one embodiment, theadult subject achieves a decrease in DAS28 score as compared to baselineafter treatment for at least twelve weeks (e.g., at week 12 oftreating). In one embodiment, the adult subject achieves a decrease inDAS28(CRP) as compared to baseline after treatment for at least 12 weeks(e.g., at week 12 of treating). In another embodiment, the adult subjectachieves a decrease in DAS28(CRP) as compared to baseline aftertreatment for at least 8 weeks (e.g., at week 8 of treating). In anotherembodiment, the adult subject achieves a decrease in DAS28(CRP) ascompared to baseline after treatment for at least 6 weeks (e.g., at week6 of treating). In another embodiment, the adult subject achieves adecrease in DAS28(CRP) as compared to baseline after treatment for atleast 4 weeks (e.g., at week 4 of treating). In another embodiment, theadult subject achieves a decrease in DAS28(CRP) as compared to baselineafter treatment for at least 2 weeks (e.g., at week 2 of treating).

In another embodiment, the adult subject receiving the treatmentachieves a low disease activity (LDA) score or clinical remission aftertreatment. In one embodiment, the LDA score or clinical remission ismeasured as a DAS28 score (in particular. DAS28(CRP)) of 3.2 or less. Inanother embodiment, the LDA score or clinical remission is measured as aDAS28(CRP) of less than 2.6. In another embodiment, the LDA score orclinical remission is assessed using Clinical Disease Activity Index(CDAI) criteria. In one embodiment, the adult subject achieves a CDAIscore of 10 or less after treatment. In another embodiment, the adultsubject achieves a CDAI score of 2.8 or less after treatment. In oneembodiment, the adult subject achieves the LDA score or clinicalremission after treatment for at least 12 weeks (e.g., at week 12 oftreating). In one embodiment, the adult subject achieves the LDA scoreor clinical remission after treatment for at least 8 weeks (e.g., atweek 8 of treating). In one embodiment, the adult subject achieves theLDA score or clinical remission after treatment for at least 6 weeks(e.g., at week 6 of treating). In one embodiment, the adult subjectachieves the LDA score or clinical remission after treatment for atleast 4 weeks (e.g., at week 4 of treating). In one embodiment, theadult subject achieves the LDA score or clinical remission aftertreatment for at least 2 weeks (e.g., at week 2 of treating).

In one embodiment, the adult subject receiving the treatment achieves achange in mean modified Total Sharp Score (mTSS). In one embodiment, theadult subject receiving the treatment achieves a change in mTSS aftertreatment for at least twelve weeks (e.g., at week 12 of treating), orafter treatment for at least twenty-four weeks (e.g., at week 24 oftreating). In one embodiment, mTSS may be determined by scoring x-raysof the hand/wrist and feet joints for erosions and joint spacenarrowing. The erosion score and narrowing score are added to determinethe total score.

In one embodiment, the adult subject receiving the treatment achieves achange in HAQ-DI score. In one embodiment, the adult subject receivingthe treatment achieves a change in HAQ-DI score after treatment for atleast twelve weeks (e.g., at week 12 of treating).

In one embodiment, the adult subject receiving the treatment achieves achange in Short Form 36 (SF-36) physical component score (PCS). In oneembodiment, the adult subject receiving the treatment achieves a changein SF-36 PCS after treatment for at least twelve weeks (e.g., at week 12of treating). SF-36 is a 36 item participant questionnaire withquestions relating to participant health and daily activities.

In one embodiment, the adult subject receiving the treatment achieves aclinical remission (CR). In one embodiment, the adult subject receivingthe treatment achieves a CR after treatment for at least twelve weeks(e.g., at week 12 of treating). In one embodiment, CR is determinedbased on DAS28 C-Reactive Protein (DAS28(CRP)) response rate. In oneembodiment, CR is a DAS28(CRP) score of less than 2.6.

In one embodiment, the adult subject receiving the treatment achieves achange in functional assessment of chronic illness therapy (FACIT-F). Inone embodiment, the adult subject receiving the treatment achieves achange in FACIT-F after treatment for at least twelve weeks (e.g., atweek 12 of treating). FACIT-F is a participant questionnaire with 13indexes rated on a 5 point scale. The indexes relate to theparticipant's level of fatigue during the past seven days.

In one embodiment, the adult subject receiving the treatment achieves achange in work instability score for rheumatoid arthritis (RA-WIS). Inone embodiment, the adult subject receiving the treatment achieves achange in RA-WIS after treatment for at least twelve weeks (e.g., atweek 12 of treating). RA-WIS is a participant questionnaire containing23 questions relating to the participant's functioning in their workenvironment.

In one embodiment, the adult subject receiving the treatment achieves achange in morning stiffness severity. In one embodiment, the adultsubject receiving the treatment achieves a change in morning stiffnessseverity after treatment for at least twelve weeks (e.g., at week 12 oftreating). Morning stiffness severity is determined by the Patient'sAssessment of Severity and Duration of Morning Stiffness questionnaire.

In one embodiment, the method or use comprises administering to thesubject about 7.5 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 (freebase), or a pharmaceutically acceptablesalt thereof or a solid state form of Compound 1 in an amount sufficientto deliver to the subject about 7.5 mg, per unit dosage form (e.g., pertablet or capsule), of Compound 1 freebase equivalent to the subject,wherein the subject achieves an ACR20 response at week 12 of treating.In another embodiment, the subject achieves an ACR20 response at week 8of treating. In another embodiment, the subject achieves an ACR20response at week 6 of treating. In another embodiment, the subjectachieves an ACR20 response at week 4 of treating. In another embodiment,the subject achieves an ACR20 response at week 2 of treating. In oneembodiment, the method or use comprises administering to the subjectabout 7.5 mg, per unit dosage form (e.g., per tablet or capsule), ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1 in an amount sufficient to deliver tothe subject about 7.5 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subjectachieves an ACR50 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 8 oftreating. In another embodiment, the subject achieves an ACR50 responseat week 6 of treating. In another embodiment, the subject achieves anACR50 response at week 4 of treating. In one embodiment, the method oruse comprises administering to the subject about 7.5 mg, per unit dosageform (e.g., per tablet or capsule), of Compound 1 (freebase), or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 7.5mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent, wherein the subject achieves an ACR70 response atweek 12 of treating. In one embodiment, the method or use comprisesadministering to the subject about 7.5 mg, per unit dosage form (e.g.,per tablet or capsule), of Compound 1 (freebase), or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 freebase equivalent,wherein the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 12 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 8 oftreating. In another embodiment, the subject achieves a decrease inDAS28(CRP) as compared to baseline at week 6 of treating. In anotherembodiment, the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 4 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 2 oftreating. In one embodiment, the method or use comprises administeringabout 7.5 mg, per unit dosage form (e.g., per tablet or capsule), of thesolid state form to the subject. In one embodiment, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or the solidstate form is in a once daily extended release formulation. In oneembodiment, the solid state form is a crystalline hydrate. In oneembodiment, the crystalline hydrate is the Freebase Hydrate Form B. Inone embodiment, the crystalline hydrate is the Freebase Hydrate Form C.In one embodiment, the solid state form is a crystalline anhydrate. Inone embodiment, the crystalline anhydrate is the Freebase Anhydrate FormD. In one embodiment, the solid state form is the Tartrate Hydrate.

In one embodiment, the method or use comprises administering to thesubject about 15 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 (freebase), or a pharmaceutically acceptable salt thereofor a solid state form of Compound 1 in an amount sufficient to deliverto the subject about 15 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subjectachieves an ACR20 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR20 response at week 8 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 6 of treating. In another embodiment, the subject achieves anACR20 response at week 4 of treating. In another embodiment, the subjectachieves an ACR20 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 15 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 15 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject achieves an ACR50response at week 12 of treating. In another embodiment, the subjectachieves an ACR50 response at week 8 of treating. In another embodiment,the subject achieves an ACR50 response at week 6 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 4 oftreating. In one embodiment, the method or use comprises administeringto the subject about 15 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 (freebase), or a pharmaceutically acceptablesalt thereof or a solid state form of Compound 1 in an amount sufficientto deliver to the subject about 15 mg, per unit dosage form (e.g., pertablet or capsule), of Compound 1 freebase equivalent, wherein thesubject achieves an ACR70 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR70 response at week 8 oftreating. In another embodiment, the subject achieves an ACR70 responseat week 6 of treating. In one embodiment, the method or use comprisesadministering to the subject about 15 mg, per unit dosage form (e.g.,per tablet or capsule), of Compound 1 (freebase), or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 in an amountsufficient to deliver to the subject about 15 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 freebase equivalent,wherein the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 12 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 8 oftreating. In another embodiment, the subject achieves a decrease inDAS28(CRP) as compared to baseline at week 6 of treating. In anotherembodiment, the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 4 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 2 oftreating. In one embodiment, the method or use comprises administeringabout 15 mg, per unit dosage form (e.g., per tablet or capsule), of thesolid state form to the subject. In one embodiment, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or the solidstate form is in a once daily extended release formulation. In oneembodiment, the solid state form is a crystalline hydrate. In oneembodiment, the crystalline hydrate is the Freebase Hydrate Form B. Inone embodiment, the crystalline hydrate is the Freebase Hydrate Form C.In one embodiment, the solid state form is a crystalline anhydrate. Inone embodiment, the crystalline anhydrate is the Freebase Anhydrate FormD. In one embodiment, the solid state form is the Tartrate Hydrate.

In one embodiment, the method or use comprises administering to thesubject about 24 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 (freebase), or a pharmaceutically acceptable salt thereofor a solid state form of Compound 1 in an amount sufficient to deliverto the subject about 24 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subjectachieves an ACR20 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR20 response at week 8 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 6 of treating. In another embodiment, the subject achieves anACR20 response at week 4 of treating. In another embodiment, the subjectachieves an ACR20 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 24 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 24 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject achieves an ACR50response at week 12 of treating. In another embodiment, the subjectachieves an ACR50 response at week 8 of treating. In another embodiment,the subject achieves an ACR50 response at week 6 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 4 oftreating. In one embodiment, the method or use comprises administeringto the subject about 24 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 (freebase), or a pharmaceutically acceptablesalt thereof or a solid state form of Compound 1 in an amount sufficientto deliver to the subject about 24 mg, per unit dosage form (e.g., pertablet or capsule), of Compound 1 freebase equivalent, wherein thesubject achieves an ACR70 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR70 response at week 8 oftreating. In another embodiment, the subject achieves an ACR70 responseat week 6 of treating. In one embodiment, the method or use comprisesadministering to the subject about 24 mg, per unit dosage form (e.g.,per tablet or capsule), of Compound 1 (freebase), or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 in an amountsufficient to deliver to the subject about 24 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 freebase equivalent,wherein the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 12 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 8 oftreating. In another embodiment, the subject achieves a decrease inDAS28(CRP) as compared to baseline at week 6 of treating. In anotherembodiment, the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 4 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 2 oftreating. In one embodiment, the method or use comprises administeringabout 24 mg, per unit dosage form (e.g., per tablet or capsule), of thesolid state form to the subject. In one embodiment, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or the solidstate form is in a once daily extended release formulation. In oneembodiment, the solid state form is a crystalline hydrate. In oneembodiment, the crystalline hydrate is the Freebase Hydrate Form B. Inone embodiment, the crystalline hydrate is the Freebase Hydrate Form C.In one embodiment, the solid state form is a crystalline anhydrate. Inone embodiment, the crystalline anhydrate is the Freebase Anhydrate FormD. In one embodiment, the solid state form is the Tartrate Hydrate.

In one embodiment, the method or use comprises administering to thesubject about 30 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 (freebase), or a pharmaceutically acceptable salt thereofor a solid state form of Compound 1 in an amount sufficient to deliverto the subject about 30 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subjectachieves an ACR20 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR20 response at week 8 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 6 of treating. In another embodiment, the subject achieves anACR20 response at week 4 of treating. In another embodiment, the subjectachieves an ACR20 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 30 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject achieves an ACR50response at week 12 of treating. In another embodiment, the subjectachieves an ACR50 response at week 8 of treating. In another embodiment,the subject achieves an ACR50 response at week 6 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 4 oftreating. In another embodiment, the subject achieves an ACR50 responseat week 2 of treating. In one embodiment, the method or use comprisesadministering to the subject about 30 mg, per unit dosage form (e.g.,per tablet or capsule), of Compound 1 (freebase), or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 in an amountsufficient to deliver to the subject about 30 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 freebase equivalent,wherein the subject achieves an ACR70 response at week 12 of treating.In another embodiment, the subject achieves an ACR70 response at week 8of treating. In one embodiment, the method or use comprisesadministering to the subject about 30 mg, per unit dosage form (e.g.,per tablet or capsule), of Compound 1 (freebase), or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 in an amountsufficient to deliver to the subject about 30 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 freebase equivalent,wherein the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 12 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 8 oftreating. In another embodiment, the subject achieves a decrease inDAS28(CRP) as compared to baseline at week 6 of treating. In anotherembodiment, the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 4 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 2 oftreating. In one embodiment, the method or use comprises administeringabout 30 mg, per unit dosage form (e.g., per tablet or capsule), of thesolid state form to the subject. In one embodiment, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or the solidstate form is in a once daily extended release formulation. In oneembodiment, the solid state form is a crystalline hydrate. In oneembodiment, the crystalline hydrate is the Freebase Hydrate Form B. Inone embodiment, the crystalline hydrate is the Freebase Hydrate Form C.In one embodiment, the solid state form is a crystalline anhydrate. Inone embodiment, the crystalline anhydrate is the Freebase Anhydrate FormD. In one embodiment, the solid state form is the Tartrate Hydrate.

In one embodiment, the method or use comprises administering to thesubject about 45 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 (freebase), or a pharmaceutically acceptable salt thereofor a solid state form of Compound 1 in an amount sufficient to deliverto the subject about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subjectachieves an ACR20 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR20 response at week 8 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 6 of treating. In another embodiment, the subject achieves anACR20 response at week 4 of treating. In another embodiment, the subjectachieves an ACR20 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 45 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 45 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject achieves an ACR50response at week 12 of treating. In another embodiment, the subjectachieves an ACR50 response at week 8 of treating. In another embodiment,the subject achieves an ACR50 response at week 6 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 4 oftreating. In one embodiment, the method or use comprises administeringto the subject about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 (freebase), or a pharmaceutically acceptablesalt thereof or a solid state form of Compound 1 in an amount sufficientto deliver to the subject about 45 mg, per unit dosage form (e.g., pertablet or capsule), of Compound 1 freebase equivalent, wherein thesubject achieves an ACR70 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR70 response at week 8 oftreating. In another embodiment, the subject achieves an ACR70 responseat week 6 of treating. In another embodiment, the subject achieves anACR70 response at week 4 of treating. In one embodiment, the method oruse comprises administering to the subject about 45 mg, per unit dosageform (e.g., per tablet or capsule), of Compound 1 (freebase), or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 45mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent, wherein the subject achieves a decrease inDAS28(CRP) as compared to baseline at week 12 of treating. In anotherembodiment, the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 8 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 6 oftreating. In another embodiment, the subject achieves a decrease inDAS28(CRP) as compared to baseline at week 4 of treating. In anotherembodiment, the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 2 of treating. In one embodiment, the method or usecomprises administering about 45 mg, per unit dosage form (e.g., pertablet or capsule), of the solid state form to the subject. In oneembodiment, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the solid state form is in a once daily extended releaseformulation. In one embodiment, the solid state form is a crystallinehydrate. In one embodiment, the crystalline hydrate is the FreebaseHydrate Form B. In one embodiment, the crystalline hydrate is theFreebase Hydrate Form C. In one embodiment, the solid state form is acrystalline anhydrate. In one embodiment, the crystalline anhydrate isthe Freebase Anhydrate Form D. In one embodiment, the solid state formis the Tartrate Hydrate.

In another embodiment, the adult subject is a subject who has had aninadequate response or intolerance to one or more disease-modifyingantirheumatic drugs (DMARDs). In one embodiment, the DMARD is aconventional synthetic DMARD (csDMARD). In another embodiment, the DMARDis a biologic DMARD (bDMARD). Examples of csDMARDs include, but are notlimited to, methotrexate (MTX), sulfasalazine, hydroxychloroquine,chloroquine, leflunomide, and azathioprine. Examples of bDMARDs include,but are not limited to, tocilizumab such as ACTEMRA™, etanercept such asp75TNFR1gG (ENBREL™ brand etanercept), adalimumab (such as HUMIRA™ brandadalimumab), and golimumab such as SIMPONI™ (golimumab). In oneembodiment, the csDMARD is MTX. In one embodiment, the bDMARD is ananti-TNF biologic. An inadequate response or intolerance to one or moreDMARDs can be measured using any of the indices described herein (e.g.,failure to achieve an ACR20 response). In one embodiment, a subjecthaving an inadequate response to a DMARD is a subject who does notachieve reduced disease activity, does not achieve an improvement inphysical function, exhibits no evidence of stopping disease progression,or who experiences disease relapse after treatment with the DMARD. Inone embodiment, a subject having an inadequate response to a DMARD is asubject who does not achieve an ACR20 response after treatment with theDMARD. In one embodiment, a subject having an inadequate tolerance(intolerance) to a DMARD is a subject who experiences toxicity orcomplicating co-morbidities after treatment with the DMARD.

In one embodiment, the adult subject is a subject who has had aninadequate response to stable methotrexate therapy. In one embodiment,the adult subject received methotrexate therapy for at least threemonths prior to treatment. In another embodiment, the adult subjectreceived a stable dose of methotrexate of about 7.5 to about 25 mg perweek for at least four weeks prior to treatment. In another embodiment,the adult subject is administered a stable dose of methotrexate (e.g.,from about 7.5 to about 25 mg per week) during treatment withCompound 1. In another embodiment, the adult subject received asupplement of folic acid for at least four weeks prior to treatment. Inanother embodiment, the adult subject is administered a supplement offolic acid during treatment.

In one embodiment, the adult subject is a subject who has had aninadequate response or intolerance to at least one anti-TNF therapy.Anti-TNF biologic agents are described elsewhere herein, and include TNFantagonists such as chimeric, humanized or human TNF antibodies,adalimumab (such as HUMIRA™ brand adalimumab), infliximab such as CA2(REMICADE™ brand infliximab), golimumab such as SIMPONI™ (golimumab),certolizumab pegol such as CIMZIA™, tocilizumab such as ACTEMRA™, CDP571, and soluble p55 or p75 TNF receptors, derivatives, thereof,etanercept such as p75TNFR1gG (ENBREL™ brand etanercept) or p55TNFR1gG(lenercept). In one embodiment, the adult subject received methotrexatetherapy for at least three months prior to treatment. In anotherembodiment, the adult subject received a stable dose of methotrexate ofabout 7.5 to about 25 mg per week for at least four weeks prior totreatment. In another embodiment, the adult subject is administered astable dose of methotrexate (e.g., from about 7.5 to about 25 mg perweek) during treatment with Compound 1. In another embodiment, the adultsubject has been treated with at least one anti-TNF biologic agent forat least three months prior to treatment with Compound 1. In anotherembodiment, the adult subject received a supplement of folic acid for atleast four weeks prior to treatment. In another embodiment, the adultsubject is administered a supplement of folic acid during treatment

In certain embodiments, the adult subject, who has had an inadequateresponse or tolerance to one or more DMARDS (including methotrexateand/or an anti-TNF biologic agent), achieves an ACR20 response, an ACR50response, an ACR70 response, and/or a decrease in DAS28(CRP) as comparedto baseline following treatment for at least twelve weeks (e.g., at week12 of treating), and/or following treatment for at least 8 weeks (e.g.,at week 8 of treating), and/or following treatment for at least 6 weeks(e.g., at week 6 of treating), and/or following treatment for at least 4weeks (e.g., at week 4 of treating), and/or following treatment for atleast 2 weeks (e.g., at week 2 of treating).

For instance, in one embodiment, the method or use comprisesadministering to the subject about 7.5 mg, per unit dosage form (e.g.,per tablet or capsule), of Compound 1 (freebase), or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 freebase equivalent,wherein the subject has had an inadequate response or intolerance to oneor more DMARDS, and the subject achieves an ACR20 response at week 12 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 8 of treating. In another embodiment, the subject achieves anACR20 response at week 6 of treating. In another embodiment, the subjectachieves an ACR20 response at week 4 of treating. In another embodiment,the subject achieves an ACR20 response at week 2 of treating. In oneembodiment, the method or use comprises administering to the subjectabout 7.5 mg, per unit dosage form (e.g., per tablet or capsule), ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1 in an amount sufficient to deliver tothe subject about 7.5 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subject has hadan inadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 50 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 8 oftreating. In another embodiment, the subject achieves an ACR50 responseat week 6 of treating. In another embodiment, the subject achieves anACR50 response at week 4 of treating. In one embodiment, the method oruse comprises administering to the subject about 7.5 mg, per unit dosageform (e.g., per tablet or capsule), of Compound 1 (freebase), or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 7.5mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent, wherein the subject has had an inadequate responseor intolerance to one or more DMARDS, and the subject achieves an ACR 70response at week 12 of treating. In one embodiment, the method or usecomprises administering to the subject about 7.5 mg, per unit dosageform (e.g., per tablet or capsule), of Compound 1 (freebase), or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 7.5mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent, wherein the subject has had an inadequate responseor intolerance to one or more DMARDS, and the subject achieves adecrease in DAS28(CRP) as compared to baseline at week 12 of treating.In another embodiment, the subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 8 of treating. In another embodiment, thesubject achieves a decrease in DAS28(CRP) as compared to baseline atweek 6 of treating. In another embodiment, the subject achieves adecrease in DAS28(CRP) as compared to baseline at week 4 of treating. Inanother embodiment, the subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 2 of treating. In one embodiment, themethod or use comprises administering about 7.5 mg, per unit dosage form(e.g., per tablet or capsule), of the solid state form to the subject.In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the solid state form is in a once dailyextended release formulation. In one embodiment, the solid state form isa crystalline hydrate. In one embodiment, the crystalline hydrate is theFreebase Hydrate Form B. In one embodiment, the crystalline hydrate isthe Freebase Hydrate Form C. In one embodiment, the solid state form isa crystalline anhydrate. In one embodiment, the crystalline anhydrate isthe Freebase Anhydrate Form D. In one embodiment, the solid state formis the Tartrate Hydrate.

In one embodiment, the method or use comprises administering to thesubject about 15 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 (freebase), or a pharmaceutically acceptable salt thereofor a solid state form of Compound 1 in an amount sufficient to deliverto the subject about 15 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subject has hadan inadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 20 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR20 response at week 8 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 6 of treating. In another embodiment, the subject achieves anACR20 response at week 4 of treating. In another embodiment, the subjectachieves an ACR20 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 15 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 15 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject has had aninadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 50 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 8 oftreating. In another embodiment, the subject achieves an ACR50 responseat week 6 of treating. In another embodiment, the subject achieves anACR50 response at week 4 of treating. In one embodiment, the method oruse comprises administering to the subject about 15 mg, per unit dosageform (e.g., per tablet or capsule), of Compound 1 (freebase), or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 15mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent, wherein the subject has had an inadequate responseor intolerance to one or more DMARDS, and the subject achieves an ACR 70response at week 12 of treating. In another embodiment, the subjectachieves an ACR70 response at week 8 of treating. In another embodiment,the subject achieves an ACR70 response at week 6 of treating. In oneembodiment, the method or use comprises administering to the subjectabout 15 mg, per unit dosage form (e.g., per tablet or capsule), ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1 in an amount sufficient to deliver tothe subject about 15 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subject has hadan inadequate response or intolerance to one or more DMARDS, and thesubject achieves a decrease in DAS28(CRP) as compared to baseline atweek 12 of treating. In another embodiment, the subject achieves adecrease in DAS28(CRP) as compared to baseline at week 8 of treating. Inanother embodiment, the subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 6 of treating. In another embodiment, thesubject achieves a decrease in DAS28(CRP) as compared to baseline atweek 4 of treating. In another embodiment, the subject achieves adecrease in DAS28(CRP) as compared to baseline at week 2 of treating. Inone embodiment, the method or use comprises administering about 15 mg,per unit dosage form (e.g., per tablet or capsule), of the solid stateform to the subject. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the solid state form is in aonce daily extended release formulation. In one embodiment, the solidstate form is a crystalline hydrate. In one embodiment, the crystallinehydrate is the Freebase Hydrate Form B. In one embodiment, thecrystalline hydrate is the Freebase Hydrate Form C. In one embodiment,the solid state form is a crystalline anhydrate. In one embodiment, thecrystalline anhydrate is the Freebase Anhydrate Form D. In oneembodiment, the solid state form is the Tartrate Hydrate.

In one embodiment, the method or use comprises administering to thesubject about 24 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 (freebase), or a pharmaceutically acceptable salt thereofor a solid state form of Compound 1 in an amount sufficient to deliverto the subject about 24 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subject has hadan inadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 20 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR20 response at week 8 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 6 of treating. In another embodiment, the subject achieves anACR20 response at week 4 of treating. In another embodiment, the subjectachieves an ACR20 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 24 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 24 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject has had aninadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 50 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 8 oftreating. In another embodiment, the subject achieves an ACR50 responseat week 6 of treating. In another embodiment, the subject achieves anACR50 response at week 4 of treating. In another embodiment, the subjectachieves an ACR50 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 24 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 24 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject has had aninadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 70 response at week 12 of treating. In oneembodiment, the method or use comprises administering to the subjectabout 24 mg, per unit dosage form (e.g., per tablet or capsule), ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1 in an amount sufficient to deliver tothe subject about 24 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subject has hadan inadequate response or intolerance to one or more DMARDS, and thesubject achieves a decrease in DAS28(CRP) as compared to baseline atweek 12 of treating. In another embodiment, the subject achieves adecrease in DAS28(CRP) as compared to baseline at week 8 of treating. Inanother embodiment, the subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 6 of treating. In another embodiment, thesubject achieves a decrease in DAS28(CRP) as compared to baseline atweek 4 of treating. In another embodiment, the subject achieves adecrease in DAS28(CRP) as compared to baseline at week 2 of treating. Inone embodiment, the method or use comprises administering about 24 mg,per unit dosage form (e.g., per tablet or capsule), of the solid stateform to the subject. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the solid state form is in aonce daily extended release formulation. In one embodiment, the solidstate form is a crystalline hydrate. In one embodiment, the crystallinehydrate is the Freebase Hydrate Form B. In one embodiment, thecrystalline hydrate is the Freebase Hydrate Form C. In one embodiment,the solid state form is a crystalline anhydrate. In one embodiment, thecrystalline anhydrate is the Freebase Anhydrate Form D. In oneembodiment, the solid state form is the Tartrate Hydrate.

In one embodiment, the method or use comprises administering to thesubject about 30 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 (freebase), or a pharmaceutically acceptable salt thereofor a solid state form of Compound 1 in an amount sufficient to deliverto the subject about 30 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subject has hadan inadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 20 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR20 response at week 8 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 6 of treating. In another embodiment, the subject achieves anACR20 response at week 4 of treating. In another embodiment, the subjectachieves an ACR20 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 30 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject has had aninadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 50 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 8 oftreating. In another embodiment, the subject achieves an ACR50 responseat week 6 of treating. In another embodiment, the subject achieves anACR50 response at week 4 of treating. In another embodiment, the subjectachieves an ACR50 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 30 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject has had aninadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 70 response at week 12 of treating. In oneembodiment, the method or use comprises administering to the subjectabout 30 mg, per unit dosage form (e.g., per tablet or capsule), ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1 in an amount sufficient to deliver tothe subject about 30 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subject has hadan inadequate response or intolerance to one or more DMARDS, and thesubject achieves a decrease in DAS28(CRP) as compared to baseline atweek 12 of treating. In another embodiment, the subject achieves adecrease in DAS28(CRP) as compared to baseline at week 8 of treating. Inanother embodiment, the subject achieves a decrease in DAS28(CRP) ascompared to baseline at week 6 of treating. In another embodiment, thesubject achieves a decrease in DAS28(CRP) as compared to baseline atweek 4 of treating. In another embodiment, the subject achieves adecrease in DAS28(CRP) as compared to baseline at week 2 of treating. Inone embodiment, the method or use comprises administering about 30 mg,per unit dosage form (e.g., per tablet or capsule), of the solid stateform to the subject. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the solid state form is in aonce daily extended release formulation. In one embodiment, the solidstate form is a crystalline hydrate. In one embodiment, the crystallinehydrate is the Freebase Hydrate Form B. In one embodiment, thecrystalline hydrate is the Freebase Hydrate Form C. In one embodiment,the solid state form is a crystalline anhydrate. In one embodiment, thecrystalline anhydrate is the Freebase Anhydrate Form D. In oneembodiment, the solid state form is the Tartrate Hydrate.

In one embodiment, the method or use comprises administering to thesubject about 45 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 (freebase), or a pharmaceutically acceptable salt thereofor a solid state form of Compound 1 in an amount sufficient to deliverto the subject about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, wherein the subject has hadan inadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 20 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR20 response at week 8 oftreating. In another embodiment, the subject achieves an ACR20 responseat week 6 of treating. In another embodiment, the subject achieves anACR20 response at week 4 of treating. In another embodiment, the subjectachieves an ACR20 response at week 2 of treating. In one embodiment, themethod or use comprises administering to the subject about 45 mg, perunit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 45 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent, wherein the subject has had aninadequate response or intolerance to one or more DMARDS, and thesubject achieves an ACR 50 response at week 12 of treating. In anotherembodiment, the subject achieves an ACR50 response at week 8 oftreating. In another embodiment, the subject achieves an ACR50 responseat week 6 of treating. In another embodiment, the subject achieves anACR50 response at week 4 of treating. In one embodiment, the method oruse comprises administering to the subject about 45 mg, per unit dosageform (e.g., per tablet or capsule), of Compound 1 (freebase), or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 45mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent, wherein the subject has had an inadequate responseor intolerance to one or more DMARDS, and the subject achieves an ACR 70response at week 12 of treating. In another embodiment, the subjectachieves an ACR70 response at week 8 of treating. In another embodiment,the subject achieves an ACR70 response at week 6 of treating. In anotherembodiment, the subject achieves an ACR70 response at week 4 oftreating. In one embodiment, the method or use comprises administeringto the subject about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 (freebase), or a pharmaceutically acceptablesalt thereof or a solid state form of Compound 1 in an amount sufficientto deliver to the subject about 45 mg, per unit dosage form (e.g., pertablet or capsule), of Compound 1 freebase equivalent, wherein thesubject has had an inadequate response or intolerance to one or moreDMARDS, and the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 12 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 8 oftreating. In another embodiment, the subject achieves a decrease inDAS28(CRP) as compared to baseline at week 6 of treating. In anotherembodiment, the subject achieves a decrease in DAS28(CRP) as compared tobaseline at week 4 of treating. In another embodiment, the subjectachieves a decrease in DAS28(CRP) as compared to baseline at week 2 oftreating. In one embodiment, the method or use comprises administeringabout 45 mg, per unit dosage form (e.g., per tablet or capsule), of thesolid state form to the subject. In one embodiment, the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or the solidstate form is in a once daily extended release formulation. In oneembodiment, the solid state form is a crystalline hydrate. In oneembodiment, the crystalline hydrate is the Freebase Hydrate Form B. Inone embodiment, the crystalline hydrate is the Freebase Hydrate Form C.In one embodiment, the solid state form is a crystalline anhydrate. Inone embodiment, the crystalline anhydrate is the Freebase Anhydrate FormD. In one embodiment, the solid state form is the Tartrate Hydrate.

In another embodiment, the adult subject is also administered a csDMARDor a bDMARD in a combination therapy, as described hereinafter. Incertain embodiments, the DMARD is MTX. In certain embodiments, the adultsubject receiving the combination therapy achieves an ACR20 response, anACR50 response, an ACR70 response, and/or a decrease in DAS28(CRP) ascompared to baseline following treatment. In particular embodiments, theadult subject receiving the combination therapy achieves an ACR20response, an ACR50 response, an ACR70 response, and/or a decrease inDAS28(CRP) as compared to baseline at week 12 of treating, and/or atweek 8 of treating, and/or at week 6 of treating, and/or at week 4 oftreating, and/or at week 2 of treating. In one embodiment, the adultsubject receiving the combination therapy is administered about 7.5 mg,per unit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 7.5 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent. In one embodiment, theadult subject receiving the combination therapy is administered about 15mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 15 mg, per unit dosage form (e.g., per tablet or capsule),of Compound 1 freebase equivalent. In one embodiment, the adult subjectreceiving the combination therapy is administered about 30 mg, per unitdosage form (e.g., per tablet or capsule), of Compound 1 (freebase), ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 30mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent. In one embodiment, the adult subject receiving thecombination therapy is administered about 45 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 (freebase), or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 45mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent. In one embodiment, the method comprisesadministering about 7.5 mg or about 15 mg or about 30 mg or about 45 mg,per unit dosage form (e.g., per tablet or capsule), of the solid stateform to the subject. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the solid state form is in aonce daily extended release formulation. In one embodiment, the solidstate form is a crystalline hydrate. In one embodiment, the crystallinehydrate is the Freebase Hydrate Form B. In one embodiment, thecrystalline hydrate is the Freebase Hydrate Form C. In one embodiment,the solid state form is a crystalline anhydrate. In one embodiment, thecrystalline anhydrate is the Freebase Anhydrate Form D. In oneembodiment, the solid state form is the Tartrate Hydrate.

In another embodiment, any of the methods of treating an adult subjecthaving moderate to severely active rheumatoid arthritis described hereinmay further comprises alleviating at least one symptom selected from thegroup consisting of bone erosion, cartilage erosion, inflammation, andvascularity. In another embodiment, the arthritis is further treated byalleviating at least one symptom selected from the group consisting ofjoint distortion, swelling, joint deformation, ankyloses on flexion, andseverely impaired movement.

In another embodiment, the present disclosure relates to a method oftreating structural damage associated with rheumatoid arthritis in anadult subject, particularly in a human subject suffering from orsusceptible to structural damage associated with rheumatoid arthritis.The method comprises administering to the subject a therapeuticallyeffective amount of Compound 1 (freebase), or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 (e.g., acrystalline hydrate or a crystalline anhydrate) as described herein,such that the structural damage in the adult subject is inhibited orlessened. In one embodiment, the method comprises administering to thesubject about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, perunit dosage form (e.g., per tablet or capsule), per day of Compound 1(freebase) or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, perunit dosage form (e.g., per tablet or capsule), per day of Compound 1freebase equivalent, such that the structural damage in the adultsubject is inhibited or lessened. In one embodiment, the methodcomprises administering to the subject about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule) of a solid state form of Compound 1, such that the structuraldamage in the adult subject is inhibited or lessened. In one embodiment,the Compound 1 (freebase) or a pharmaceutically acceptable salt thereofor the solid state form of Compound 1 is administered to the subjectorally QD (once daily). In one embodiment, the structural damage isselected from the group consisting of loss of bone and/or cartilage,bone erosion, joint space narrowing as measured by radiography, andcombinations thereof. In one embodiment, the structural damaged isinhibited or lessened when the structural damage is reduced by at least20%, or at least 25%, or at least 30%, or at least 50%. In otherembodiments, structural damage is inhibited or lessened when there is nofurther radiographic progression of the structural damage. In certainembodiments, structural joint damage can be assessed radiographicallyand expressed as change in Total Sharp Score (TSS) and its components,the erosion score and Joint Space Narrowing (JSN) score, for example, atweek 12 compared to baseline. In another aspect, the disclosure relatesto a solid state form (and in particular a crystalline hydrate) ofCompound 1, as described in the present disclosure, for use in treatmentof structural damage associated with rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto rheumatoid arthritis. In one embodiment, the solid state form is acrystalline hydrate. In one embodiment, the crystalline hydrate is theFreebase Hydrate Form B. In one embodiment, the crystalline hydrate is ahemihydrate. In one embodiment, the hemihydrate is Freebase Hydrate FormC. In one embodiment, the solid state form is a crystalline anhydrate.In one embodiment, the crystalline anhydrate is Freebase Anhydrate FormD. In one embodiment, the stolid state form is Tartrate Hydrate. In oneembodiment, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the crystalline hydrate is in a once daily extendedrelease formulation. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrate isin a once daily extended release formulation, and the formulationdelivers about 7.5 mg or about 15 mg or about 30 mg or about 45 mg perunit dosage form (e.g., per tablet or capsule) of Compound 1 (freebaseequivalent) orally QD (once daily).

In another aspect, the disclosure relates to Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 (e.g., a crystalline hydrate or crystalline anhydrate), asdescribed in the present disclosure for use in treatment of structuraldamage associated with rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tostructural damage associated with rheumatoid arthritis, such that thestructural damage in the adult subject is inhibited or lessened, the usecomprising administering to the subject a therapeutically effectiveamount of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In one embodiment, thesolid state form is a crystalline hydrate. In one embodiment, thecrystalline hydrate is Freebase Hydrate Form B. In one embodiment, thecrystalline hydrate is a hemihydrate. In one embodiment, the hemihydrateis Freebase Hydrate Form C. In one embodiment, the solid state form is acrystalline anhydrate. In one embodiment, the crystalline anhydrate isFreebase Anhydrate Form D. In one embodiment, the Compound 1 (freebase)or a pharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation. In oneembodiment, the formulation delivers about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg per unit dosage form (e.g., per tablet orcapsule) of Compound 1 (freebase equivalent) or a solid state form ofCompound 1 orally QD (once daily).

In one embodiment, the present disclosure is directed to a method oftreating structural damage associated with rheumatoid arthritis in anadult subject, particularly in a human subject suffering from orsusceptible to structural damage associated with rheumatoid arthritis,the method comprising administering to the subject about 7.5 mg, perunit dosage form (e.g., per tablet or capsule), per day of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 7.5 mg, per unit dosage form (e.g., per tablet orcapsule), per day of Compound 1 freebase equivalent, such that thestructural damage in the adult subject is inhibited or lessened. In oneembodiment, the method comprises administering to the subject about 7.5mg, per unit dosage form (e.g., per tablet or capsule), per day of asolid state form of Compound 1. In another aspect, the disclosurerelates to Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1, for use in treatment ofstructural damage associated with rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto structural damage associated with rheumatoid arthritis, such that thestructural damage in the adult subject is inhibited or lessened, the usecomprising administering to the subject about 7.5 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one embodiment, the solid state form is a crystallinehydrate. In one embodiment, the crystalline hydrate is the FreebaseHydrate Form B. In one embodiment, the crystalline hydrate is theFreebase Hydrate Form C. In one embodiment, the solid state form is acrystalline anhydrate. In one embodiment, the crystalline anhydrate isthe Freebase Anhydrate Form D. In one embodiment, the solid state formis the Tartrate Hydrate. In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is administered orally QD (once daily). In one embodiment,the Compound 1 freebase or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the structural damage is selected fromthe group consisting of loss of bone and/or cartilage, bone erosion,joint space narrowing as measured by radiography, and combinationsthereof.

In one embodiment, the present disclosure is directed to a method oftreating structural damage associated with rheumatoid arthritis in anadult subject, particularly in a human subject suffering from orsusceptible to structural damage associated with rheumatoid arthritis,the method comprising administering to the subject about 15 mg, per unitdosage form (e.g., per tablet or capsule), per day of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 15 mg, per unit dosage form (e.g., per tablet or capsule),per day of Compound 1 freebase equivalent, such that the structuraldamage in the adult subject is inhibited or lessened. In one embodiment,the method comprises administering to the subject about 15 mg, per unitdosage form (e.g., per tablet or capsule), per day of a solid state formof Compound 1. In another aspect, the disclosure relates to Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1, for use in treatment of structural damage associatedwith rheumatoid arthritis in an adult subject, particularly in a humansubject suffering from or susceptible to structural damage associatedwith rheumatoid arthritis, such that the structural damage in the adultsubject is inhibited or lessened, the use comprising administering tothe subject about 15 mg, per unit dosage form (e.g., per tablet orcapsule) of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In one embodiment, thesolid state form is a crystalline hydrate. In one embodiment, thecrystalline hydrate is the Freebase Hydrate Form B. In one embodiment,the crystalline hydrate is the Freebase Hydrate Form C. In oneembodiment, the solid state form is a crystalline anhydrate. In oneembodiment, the crystalline anhydrate is the Freebase Anhydrate Form D.In one embodiment, the solid state form is the Tartrate Hydrate. In oneembodiment, the Compound 1 freebase or a pharmaceutically acceptablesalt thereof or the solid state form of Compound 1 is administeredorally QD (once daily). In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation. In oneembodiment, the structural damage is selected from the group consistingof loss of bone and/or cartilage, bone erosion, joint space narrowing asmeasured by radiography, and combinations thereof.

In one embodiment, the present disclosure is directed to a method oftreating structural damage associated with rheumatoid arthritis in anadult subject, particularly in a human subject suffering from orsusceptible to structural damage associated with rheumatoid arthritis,the method comprising administering to the subject about 30 mg, per unitdosage form (e.g., per tablet or capsule), per day of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 30 mg, per unit dosage form (e.g., per tablet or capsule),per day of Compound 1 freebase equivalent, such that the structuraldamage in the adult subject is inhibited or lessened. In one embodiment,the method comprises administering to the subject about 30 mg, per unitdosage form (e.g., per tablet or capsule), per day of a solid state formof Compound 1. In another aspect, the disclosure relates to Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1, for use in treatment of structural damage associatedwith rheumatoid arthritis in an adult subject, particularly in a humansubject suffering from or susceptible to structural damage associatedwith rheumatoid arthritis, such that the structural damage in the adultsubject is inhibited or lessened, the use comprising administering tothe subject about 30 mg, per unit dosage form (e.g., per tablet orcapsule) of Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form of Compound 1. In one embodiment, thesolid state form is a crystalline hydrate. In one embodiment, thecrystalline hydrate is the Freebase Hydrate Form B. In one embodiment,the crystalline hydrate is the Freebase Hydrate Form C. In oneembodiment, the solid state form is a crystalline anhydrate. In oneembodiment, the crystalline anhydrate is the Freebase Anhydrate Form D.In one embodiment, the solid state form is the Tartrate Hydrate. In oneembodiment, the Compound 1 freebase or a pharmaceutically acceptablesalt thereof or the solid state form of Compound 1 is administeredorally QD (once daily). In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation. In oneembodiment, the structural damage is selected from the group consistingof loss of bone and/or cartilage, bone erosion, joint space narrowing asmeasured by radiography, and combinations thereof.

In one embodiment, the present disclosure is directed to a method oftreating structural damage associated with rheumatoid arthritis in anadult subject, particularly in a human subject suffering from orsusceptible to structural damage associated with rheumatoid arthritis,the method comprising administering to the subject about 45 mg, per unitdosage form (e.g., per tablet or capsule), per day of Compound 1(freebase), or a pharmaceutically acceptable salt thereof or a solidstate form of Compound 1 in an amount sufficient to deliver to thesubject about 45 mg, per unit dosage form (e.g., per tablet or capsule),per day of Compound 1 freebase equivalent, such that the structuraldamage in the adult subject is inhibited or lessened. In one embodiment,the method comprises administering to the subject about 45 mg, per unitdosage form (e.g., per tablet or capsule), per day of a solid state formof Compound 1. In another aspect, the disclosure relates to Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1, for use in treatment of structural damage associatedwith rheumatoid arthritis in an adult subject, particularly in a humansubject suffering from or susceptible to structural damage associatedwith rheumatoid arthritis, such that the structural damage in the adultsubject is inhibited or lessened, the use comprising administering tothe subject 45 mg, per unit dosage form (e.g., per tablet or capsule) ofCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1. In one embodiment, the solid state formis a crystalline hydrate. In one embodiment, the crystalline hydrate isthe Freebase Hydrate Form B. In one embodiment, the crystalline hydrateis the Freebase Hydrate Form C. In one embodiment, the solid state formis a crystalline anhydrate. In one embodiment, the crystalline anhydrateis the Freebase Anhydrate Form D. In one embodiment, the solid stateform is the Tartrate Hydrate. In one embodiment, the Compound 1 freebaseor a pharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is administered orally QD (once daily). In one embodiment,the Compound 1 freebase or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the structural damage is selected fromthe group consisting of loss of bone and/or cartilage, bone erosion,joint space narrowing as measured by radiography, and combinationsthereof.

In another embodiment, the present disclosure is directed to a method ofreducing signs and symptoms of rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tomoderately to severely active rheumatoid arthritis. The method comprisesadministering to the subject a therapeutically effective amount ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora solid state form of Compound 1 (e.g., a crystalline hydrate or acrystalline anhydrate) as described herein. In one embodiment, themethod comprises administering to the subject about 7.5 mg or about 15mg or about 30 mg or about 45 mg, per unit dosage form (e.g., per tabletor capsule), per day of Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), per day of Compound 1 freebase equivalent. In one embodiment,the method comprises administering to the subject about 7.5 mg or about15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g., pertablet or capsule) of a solid state form of Compound 1. In oneembodiment, the Compound 1 (freebase) or a pharmaceutically acceptablesalt thereof or the solid state form of Compound 1 is administered tothe subject orally QD (once daily). In another aspect, the disclosurerelates to Compound 1 freebase or a pharmaceutically acceptable saltthereof or a solid state form (and in particular a crystalline hydrate)of Compound 1, as described in the present disclosure, for use inreducing signs and symptoms of rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tomoderate to severely active rheumatoid arthritis, the use comprisingadministering to the subject a therapeutically effective amount ofCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form (and in particular a crystalline hydrate) ofCompound 1. In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation. In oneembodiment, the formulation delivers about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg per unit dosage form (e.g., per tablet orcapsule) of Compound 1 (freebase equivalent) or the solid state form ofCompound 1 to the subject orally QD (once daily). In one embodiment, thesolid state form is a crystalline hydrate. In one embodiment, thecrystalline hydrate is the Freebase Hydrate Form B. In one embodiment,the crystalline hydrate is the Freebase Hydrate Form C. In oneembodiment, the solid state form is a crystalline anhydrate. In oneembodiment, the crystalline anhydrate is the Freebase Anhydrate Form D.In one embodiment, the solid state form is the Tartrate Hydrate.

In one embodiment, the present disclosure is directed to a method ofreducing the signs and symptoms of rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto moderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 7.5 mg, per unit dosageform (e.g., per tablet or capsule), per day of Compound 1 (freebase), ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 7.5mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent. In one embodiment, the method comprisesadministering to the subject about 7.5 mg, per unit dosage form (e.g.,per tablet or capsule), per day of a solid state form of Compound 1. Inanother aspect, the disclosure relates to Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 for use in reducing signs and symptoms of rheumatoidarthritis in an adult subject, particularly in a human subject sufferingfrom or susceptible to moderate to severely active rheumatoid arthritis,the use comprising administering to the subject about 7.5 mg, per unitdosage form (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one embodiment, the solid state form is a crystallinehydrate. In one embodiment, the crystalline hydrate is the FreebaseHydrate Form B. In one embodiment, the crystalline hydrate is ahemihydrate. In one embodiment, the hemihydrate is the Freebase HydrateForm C. In one embodiment, the solid state form is a crystallineanhydrate. In one embodiment, the crystalline anhydrate is the FreebaseAnhydrate Form D. In one embodiment, the solid state form is theTartrate Hydrate. In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is administered orally QD (once daily). In one embodiment,the Compound 1 freebase or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation, and theformulation delivers about 7.5 mg per unit dosage form (e.g., per tabletor capsule) of Compound 1 (freebase equivalent) or the solid state formof Compound 1 orally QD (once daily) to the subject.

In one embodiment, the present disclosure is directed to a method ofreducing the signs and symptoms of rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto moderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 15 mg, per unit dosageform (e.g., per tablet or capsule), per day of Compound 1 (freebase) ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 15mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent. In one embodiment, the method comprisesadministering to the subject about 15 mg, per unit dosage form (e.g.,per tablet or capsule), per day of a solid state form of Compound 1. Inanother aspect, the disclosure relates to Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 for use in reducing signs and symptoms of rheumatoidarthritis in an adult subject, particularly in a human subject sufferingfrom or susceptible to moderate to severely active rheumatoid arthritis,the use comprising administering to the subject, about 15 mg, per unitdosage form (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one embodiment, the solid state form is a crystallinehydrate. In one embodiment, the crystalline hydrate is a hemihydrate. Inone embodiment, the hemihydrate is Freebase Hydrate Form C. In oneembodiment, the crystalline hydrate is the Freebase Hydrate Form B. Inone embodiment, the solid state form is a crystalline anhydrate. In oneembodiment, the crystalline anhydrate is the Freebase Anhydrate Form D.In one embodiment, the solid state form is the Tartrate Hydrate. In oneembodiment, the Compound 1 freebase or the solid state form of Compound1 is administered orally QD (once daily). In one embodiment, theCompound 1 (freebase) or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation, and theformulation delivers about 15 mg per unit dosage form (e.g., per tabletor capsule) of Compound 1 (freebase equivalent) or the solid state formof Compound 1 orally QD (once daily) to the subject.

In another embodiment, the present disclosure is directed to a method ofreducing signs and symptoms of rheumatoid arthritis in an adult subject,particularly in a human subject suffering from or susceptible tomoderately to severely active rheumatoid arthritis. The method comprisesadministering to the subject about 30 mg, per unit dosage form (e.g.,per tablet or capsule), per day of Compound 1 (freebase) or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 30mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent. In one embodiment, the method comprisesadministering to the subject about 30 mg, per unit dosage form (e.g.,per tablet or capsule), per day of a solid state form of Compound 1. Inanother aspect, the disclosure relates to Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 for use in reducing signs and symptoms of rheumatoidarthritis in an adult subject, particularly in a human subject sufferingfrom or susceptible to moderate to severely active rheumatoid arthritis,the use comprising administering to the subject about 30 mg, per unitdosage form (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one embodiment, the solid state form is a crystallinehydrate. In one embodiment, the crystalline hydrate is a hemihydrate. Inone embodiment, the hemihydrate is Freebase Hydrate Form C. In oneembodiment, the crystalline hydrate is the Freebase Hydrate Form B. Inone embodiment, the solid state form is a crystalline anhydrate. In oneembodiment, the crystalline anhydrate is the Freebase Anhydrate Form D.In one embodiment, the solid state form is the Tartrate Hydrate. In oneembodiment, the Compound 1 freebase or a pharmaceutically acceptablesalt thereof or the solid state form of Compound 1 is administeredorally QD (once daily). In one embodiment, the Compound 1 (freebase) orthe crystalline hydrate is in a once daily extended release formulation.In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the solid state form of Compound 1 is in aonce daily extended release formulation, and the formulation deliversabout 30 mg per unit dosage form (e.g., per tablet or capsule) ofCompound 1 (freebase equivalent) or the solid state form of Compound 1orally QD (once daily) to the subject.

In one embodiment, the present disclosure is directed to a method ofreducing the signs and symptoms of rheumatoid arthritis in an adultsubject, particularly in a human subject suffering from or susceptibleto moderately to severely active rheumatoid arthritis, the methodcomprising administering to the subject about 45 mg, per unit dosageform (e.g., per tablet or capsule), per day of Compound 1 (freebase), ora pharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 45mg, per unit dosage form (e.g., per tablet or capsule), per day ofCompound 1 freebase equivalent. In one embodiment, the method comprisesadministering to the subject about 45 mg, per unit dosage form (e.g.,per tablet or capsule), per day of a solid state form of Compound 1. Inanother aspect, the disclosure relates to Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 for use in reducing signs and symptoms of rheumatoidarthritis in an adult subject, particularly in a human subject sufferingfrom or susceptible to moderate to severely active rheumatoid arthritis,the use comprising administering to the subject about 45 mg, per unitdosage form (e.g., per tablet or capsule) of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1. In one embodiment, the solid state form is a crystallinehydrate. In one embodiment, the crystalline hydrate is the FreebaseHydrate Form B. In one embodiment, the crystalline hydrate is ahemihydrate. In one embodiment, the hemihydrate is the Freebase HydrateForm C. In one embodiment, the solid state form is a crystallineanhydrate. In one embodiment, the crystalline anhydrate is the FreebaseAnhydrate Form D. In one embodiment, the solid state form is theTartrate Hydrate. In one embodiment, the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is administered orally QD (once daily). In one embodiment,the Compound 1 freebase or a pharmaceutically acceptable salt thereof orthe solid state form of Compound 1 is in a once daily extended releaseformulation. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1 is in a once daily extended release formulation, and theformulation delivers about 45 mg per unit dosage form (e.g., per tabletor capsule) of Compound 1 (freebase equivalent) or the solid state formof Compound 1 orally QD (once daily) to the subject.

In another aspect, the disclosure relates to a solid state form (and inparticular a crystalline hydrate) of Compound 1, as described in thepresent disclosure, for use in reducing signs and symptoms of rheumatoidarthritis in an adult subject, particularly in a human subject sufferingfrom or susceptible to rheumatoid arthritis.

In another embodiment, any of the methods of reducing signs and symptomsof rheumatoid arthritis described herein may further comprisesalleviating at least one symptom selected from the group consisting ofbone erosion, cartilage erosion, inflammation, and vascularity. Inanother embodiment, the arthritis is further treated by alleviating atleast one symptom selected from the group consisting of jointdistortion, swelling, joint deformation, ankyloses on flexion, andseverely impaired movement.

In another embodiment, the Compound 1 freebase or a pharmaceuticallyacceptable salt thereof and/or solid state forms of Compound 1 used inany of the methods set forth herein may be administered to the subjectin a once daily extended release solid oral dosage form. In particular,in one embodiment, the methods comprise once daily administration to thesubject of an extended release (e.g., modified release) solid oraldosage form comprising the Compound 1 freebase or a pharmaceuticallyacceptable salt thereof or the solid state form of Compound 1, and apharmaceutically acceptable polymeric carrier substantially contributingto the modification of the release of the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1. In one aspect, the dosage form sustains release of theCompound 1 freebase or a pharmaceutically acceptable salt thereof or thesolid state form of Compound 1 for from about 4 hours to about 24 hoursfollowing entry of the dosage form into a use environment. In oneembodiment, the dosage form has a release rate of not more than about60% after passage of about 4 hours following entry of the dosage forminto a use environment. The term “entry into a use environment” refersto contact of the dosage form with gastric fluids of the subject to whomit is administered. As used herein, the term “release rate” refers tothe percentage of the active ingredient (e.g., Compound 1 or a solidstate form of Compound 1) in the dosage form that is released in thegiven time period, and under the specified conditions. In oneembodiment, the dosage form comprises about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 (freebase), or a pharmaceutically acceptablesalt thereof or a solid state form of Compound 1 in an amount sufficientto deliver to the subject about 7.5 mg or about 15 mg or about 30 mg orabout 45 mg, per unit dosage form (e.g., per tablet or capsule), per dayof Compound 1 freebase equivalent. In one embodiment, the dosage formcomprises about 7.5 mg or about 15 mg or about 30 mg or about 45 mg, perunit dosage form (e.g., per tablet or capsule), per day of a solid stateform of Compound 1. In one embodiment, the solid state form is FreebaseHydrate Form B. In one embodiment, the solid state form is FreebaseHydrate Form C. In one embodiment, the solid state form is FreebaseAnhydrate Form D. In one embodiment, the solid state form is TartrateHydrate. In one embodiment, the pharmaceutically acceptable polymericcarrier is a release control polymer, as set forth herein.

Thus, in one aspect, the dosage form sustains release of the Compound 1freebase or a pharmaceutically acceptable salt thereof or the solidstate form of Compound 1 for from about 4 hours to about 24 hours. Inone embodiment, the dosage form releases the active ingredient (i.e.,Compound 1 or a solid state form of Compound 1), at a release rate ofnot more than about 25%, or from about 10% to about 25%, or from about15% to about 20%, or about 20% after passage of about 1 hour followingentry into the use environment. In one embodiment, the dosage formreleases the active ingredient at a release rate of not more than about40%, or from about 20% to about 40%, or from about 25% to about 35%after passage of about 2 hours following entry into the use environment.In one embodiment, the dosage form releases the active ingredient at arelease rate of not more than about 60%, or from about 30% to about 60%,or from about 40% to about 60%, or from about 45% to about 55% afterpassage of about 4 hours following entry into the use environment. Inone embodiment, the dosage form releases the active ingredient at arelease rate of not more than about 70% or from about 40% to about 70%,or from about 55% to about 70% after passage of about 6 hours followingentry into the use environment. In one embodiment, the dosage formreleases the active ingredient at a release rate of not more than about80% or from about 55% to about 80%, or from about 60% to about 80% afterpassage of about 6 hours following entry into the use environment. Inone embodiment, the dosage form releases the active ingredient at arelease rate of not more than about 80%, or not less than about 50%, ornot less than about 60%, or not less than about 70%, or not less thanabout 75%, or from about 50% to about 80%, or from about 60% to about80%, or from about 65% to about 80% after passage of about 8 hoursfollowing entry into the use environment. In one embodiment, the dosageform releases the active ingredient at a release rate of not less thanabout 55%, or not less than about 60% or not less than about 70%, or notless than about 80%, or not less than about 85%, or from about 55% toabout 90%, or from about 70% to about 90% after passage of about 10hours following entry into the use environment. In one embodiment, thedosage form releases the active ingredient at a release rate of not lessthan about 65%, or not less than about 70%, or not less than about 80%,or not less than about 90%, or from about 65% to about 99%, or fromabout 80% to about 99%, or from about 90% to about 99% after passage ofabout 16 hours following entry into the use environment. In oneembodiment, the dosage form releases the active ingredient at a releaserate of not less than about 70%, or not less than about 80%, or not lessthan about 90%, or from about 70% to 100%, or from about 80% to 100%after passage of about 20 hours following entry into the useenvironment. In one aspect, the dosage form has a release rate of notmore than about 60% after passage of about 4 hours following entry ofthe dosage form into a use environment, from about 50% to about 80%after passage of about 8 hours following entry of the dosage form into ause environment, from about 55% to about 90% after passage of about 10hours following entry of the dosage form into a use environment, andfrom about 70% to 100% after passage of about 20 hours following entryof the dosage form into a use environment.

In one embodiment, the present disclosure is directed to a method oftreating a condition selected from the group consisting of rheumatoidarthritis, juvenile idiopathic arthritis, Crohn's disease, ulcerativecolitis, psoriasis, plaque psoriasis, nail psoriasis, psoriaticarthritis, ankylosing spondylitis, alopecia areata, hidradenitissuppurativa, atopic dermatitis, and systemic lupus erythematosus, themethod comprising once daily administration to a subject suffering fromor susceptible to the condition, of an extended release solid oraldosage form comprising about 7.5 mg or about 15 mg or about 30 mg orabout 45 mg, per unit dosage form (e.g., per tablet or capsule), ofCompound 1 freebase or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 in an amount sufficient to deliver to thesubject about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg,per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase equivalent, and a pharmaceutically acceptable polymeric carriersubstantially contributing to the modification of the release of theCompound 1 freebase or a pharmaceutically acceptable salt thereof or thesolid state form of Compound 1, wherein the dosage form sustains releaseof the Compound 1 freebase or a pharmaceutically acceptable salt thereofor the solid state form of Compound 1 for from about 4 to about 24 hoursfollowing entry of the dosage form into a use environment, wherein thedosage form has a release rate of not more than about 60% after passageof about 4 hours following said entry into said use environment. In oneembodiment, the dosage form comprises about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of a solid state form of Compound 1. In one embodiment, thesolid state form is Freebase Hydrate Form B. In one embodiment, thesolid state form is Freebase Hydrate Form C. In one embodiment, thesolid state form is Freebase Anhydrate Form D. In one embodiment, thesolid state form is Tartrate Hydrate. In one embodiment, the dosage formfurther has a release rate of from about 50% to about 80% after passageof about 8 hours following entry of the dosage form into a useenvironment, from about 55% to about 90% after passage of about 10 hoursfollowing entry of the dosage form into a use environment, and/or fromabout 70% to 100% after passage of about 20 hours following entry of thedosage form into a use environment.

In another aspect, the disclosure is directed to an extended releasesolid oral dosage form comprising Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 for use in treating a condition selected from the groupconsisting of rheumatoid arthritis, juvenile idiopathic arthritis,Crohn's disease, ulcerative colitis, psoriasis, plaque psoriasis, nailpsoriasis, psoriatic arthritis, ankylosing spondylitis, alopecia areata,hidradenitis suppurativa, atopic dermatitis, and systemic lupuserythematosus, the use comprising once daily administration to a subjectsuffering from or susceptible to the condition, of the extended releasesolid oral dosage form, wherein the solid dosage form comprises about7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unit dosageform (e.g., per tablet or capsule) of Compound 1 freebase, or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 7.5mg, or about 15 mg, or about 30 mg, or about 45 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 freebase equivalent, and apharmaceutically acceptable polymeric carrier substantially contributingto the modification of the release of the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1, wherein the dosage form sustains release of the Compound 1freebase or a pharmaceutically acceptable salt thereof or the solidstate form of Compound 1 for from about 4 to about 24 hours followingentry of the dosage form into a use environment, wherein the dosage formhas a release rate of not more than about 60% after passage of about 4hours following said entry into said use environment. In one embodiment,the dosage form comprises about 7.5 mg or about 15 mg or about 30 mg orabout 45 mg, per unit dosage form (e.g., per tablet or capsule), of asolid state form of Compound 1. In one embodiment, the solid state formis Freebase Hydrate Form B. In one embodiment, the solid state form isFreebase Hydrate Form C. In one embodiment, the solid state form isFreebase Anhydrate Form D. In one embodiment, the solid state form isTartrate Hydrate. In one embodiment, the dosage form further has arelease rate of from about 50% to about 80% after passage of about 8hours following entry of the dosage form into a use environment, fromabout 55% to about 90% after passage of about 10 hours following entryof the dosage form into a use environment, and/or from about 70% to 100%after passage of about 20 hours following entry of the dosage form intoa use environment.

In another embodiment, the disclosure is directed to a method oftreating an adult subject having moderate to severely active rheumatoidarthritis, the method comprising once daily administration to thesubject, particularly a human subject suffering from or susceptible torheumatoid arthritis, of an extended release solid oral dosage formcomprising about 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg,per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1 in an amount sufficient to deliver to the subjectabout 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg, per unitdosage form (e.g., per tablet or capsule), of Compound 1 freebaseequivalent, and a pharmaceutically acceptable polymeric carriersubstantially contributing to the modification of the release of theCompound 1 freebase or a pharmaceutically acceptable salt thereof or thesolid state form of Compound 1, wherein the dosage form sustains releaseof the Compound 1 freebase or a pharmaceutically acceptable salt thereofor the solid state form of Compound 1 for from about 4 to about 24 hoursfollowing entry of the dosage form into a use environment, wherein thedosage form has a release rate of not more than about 60% after passageof about 4 hours following said entry into said use environment. In oneembodiment, the dosage form comprises about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of a solid state form of Compound 1. In one embodiment, thesolid state form is Freebase Hydrate Form B. In one embodiment, thesolid state form is Freebase Hydrate Form C. In one embodiment, thesolid state form is Freebase Anhydrate Form D. In one embodiment, thesolid state form is Tartrate Hydrate. In one embodiment, the dosage formfurther has a release rate of from about 50% to about 80% after passageof about 8 hours following entry of the dosage form into a useenvironment, from about 55% to about 90% after passage of about 10 hoursfollowing entry of the dosage form into a use environment, and/or fromabout 70% to 100% after passage of about 20 hours following entry of thedosage form into a use environment. In one embodiment, the subject hassymptoms selected from the group consisting of at least 6 swollenjoints, at least 6 tender joints, and combinations thereof prior totreating.

In another aspect, the disclosure is directed to an extended releasesolid oral dosage form comprising Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 for use in treating an adult subject having moderate toseverely active rheumatoid arthritis, the use comprising once dailyadministration to the subject, particularly a subject suffering from orsusceptible to moderately to severely active rheumatoid arthritis, ofthe extended release solid oral dosage form, wherein the solid dosageform comprises about 7.5 mg or about 15 mg or about 30 mg or about 45mg, per unit dosage form (e.g., per tablet or capsule) of Compound 1freebase or a pharmaceutically acceptable salt thereof, or a solid stateform of Compound 1 in an amount sufficient to deliver to the subjectabout 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg, per unitdosage form (e.g., per tablet or capsule), of Compound 1 freebaseequivalent, and a pharmaceutically acceptable polymeric carriersubstantially contributing to the modification of the release of theCompound 1 freebase or a pharmaceutically acceptable salt thereof or thesolid state form of Compound 1, wherein the dosage form sustains releaseof the Compound 1 freebase or a pharmaceutically acceptable salt thereofor the solid state form of Compound 1 for from about 4 to about 24 hoursfollowing entry of the dosage form into a use environment, wherein thedosage form has a release rate of not more than about 60% after passageof about 4 hours following said entry into said use environment. In oneembodiment, the dosage form comprises about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of a solid state form of Compound 1. In one embodiment, thesolid state form is Freebase Hydrate Form B. In one embodiment, thesolid state form is Freebase Hydrate Form C. In one embodiment, thesolid state form is Freebase Anhydrate Form D. In one embodiment, thesolid state form is Tartrate Hydrate. In one embodiment, the dosage formfurther has a release rate of from about 50% to about 80% after passageof about 8 hours following entry of the dosage form into a useenvironment, from about 55% to about 90% after passage of about 10 hoursfollowing entry of the dosage form into a use environment, and/or fromabout 70% to 100% after passage of about 20 hours following entry of thedosage form into a use environment. In one embodiment, the subject hassymptoms selected from the group consisting of at least 6 swollenjoints, at least 6 tender joints, and combinations thereof prior totreating.

In one embodiment, the disclosure is directed to a method of treatingstructural damage associated with rheumatoid arthritis in an adultsubject, the method comprising once daily administration to the subject,particularly a human subject suffering from or susceptible to rheumatoidarthritis, of an extended release solid oral dosage form comprisingabout 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg, per unitdosage form (e.g., per tablet or capsule), of Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 in an amount sufficient to deliver to the subject about 7.5mg, or about 15 mg, or about 30 mg, or about 45 mg, per unit dosage form(e.g., per tablet or capsule), of Compound 1 freebase or apharmaceutically acceptable salt thereof equivalent, and apharmaceutically acceptable polymeric carrier substantially contributingto the modification of the release of the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1, wherein the dosage form sustains release of the Compound 1freebase or a pharmaceutically acceptable salt thereof or the solidstate form of Compound 1 for from about 4 to about 24 hours followingentry of the dosage form into a use environment, wherein the dosage formhas a release rate of not more than about 60% after passage of about 4hours following said entry into said use environment. In one embodiment,the dosage form comprises about 7.5 mg or about 15 mg or about 30 mg orabout 45 mg, per unit dosage form (e.g., per tablet or capsule), of asolid state form of Compound 1. In one embodiment, the solid state formis Freebase Hydrate Form B. In one embodiment, the solid state form isFreebase Hydrate Form C. In one embodiment, the solid state form isFreebase Anhydrate Form D. In one embodiment, the solid state form isTartrate Hydrate. In one embodiment, the dosage form further has arelease rate of from about 50% to about 80% after passage of about 8hours following entry of the dosage form into a use environment, fromabout 55% to about 90% after passage of about 10 hours following entryof the dosage form into a use environment, and/or from about 70% to 100%after passage of about 20 hours following entry of the dosage form intoa use environment.

In another aspect, the disclosure is directed to an extended releasesolid oral dosage form comprising Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 for use in treating structural damage associated withrheumatoid arthritis in an adult subject, the use comprising once dailyadministration to the subject, particularly a subject suffering from orsusceptible to structural damage associated with rheumatoid arthritis,of the extended release solid oral dosage form, wherein the solid dosageform comprises about 7.5 mg or about 15 mg or about 30 mg or about 45mg, per unit dosage form (e.g., per tablet or capsule) of Compound 1freebase, or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1 in an amount sufficient to deliver to the subjectabout 7.5 mg, or about 15 mg, or about 30 mg, or about 45 mg, per unitdosage form (e.g., per tablet or capsule), of Compound 1 freebaseequivalent, and a pharmaceutically acceptable polymeric carriersubstantially contributing to the modification of the release of theCompound 1 freebase or a pharmaceutically acceptable salt thereof or thesolid state form of Compound 1, wherein the dosage form sustains releaseof the Compound 1 freebase or a pharmaceutically acceptable salt thereofor the solid state form of Compound 1 for from about 4 to about 24 hoursfollowing entry of the dosage form into a use environment, wherein thedosage form has a release rate of not more than about 60% after passageof about 4 hours following said entry into said use environment. In oneembodiment, the dosage form comprises about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of a solid state form of Compound 1. In one embodiment, thesolid state form is Freebase Hydrate Form B. In one embodiment, thesolid state form is Freebase Hydrate Form C. In one embodiment, thesolid state form is Freebase Anhydrate Form D. In one embodiment, thesolid state form is Tartrate Hydrate. In one embodiment, the dosage formfurther has a release rate of from about 50% to about 80% after passageof about 8 hours following entry of the dosage form into a useenvironment, from about 55% to about 90% after passage of about 10 hoursfollowing entry of the dosage form into a use environment, and/or fromabout 70% to 100% after passage of about 20 hours following entry of thedosage form into a use environment.

In one embodiment, the disclosure is directed to a method of reducingsigns and symptoms of rheumatoid arthritis in an adult subject, themethod comprising once daily administration to the subject, particularlya human subject suffering from or susceptible to moderately to severelyactive rheumatoid arthritis, of an extended release solid oral dosageform comprising about 7.5 mg or about 15 mg or about 30 mg or about 45mg, per unit dosage form (e.g., per tablet or capsule), of Compound 1freebase or a pharmaceutically acceptable salt thereof or a solid stateform of Compound 1 in an amount sufficient to deliver to the subjectabout 7.5 mg or about 15 mg or about 30 mg or about 45 mg, per unitdosage form (e.g., per tablet or capsule), of Compound 1 freebaseequivalent, and a pharmaceutically acceptable polymeric carriersubstantially contributing to the modification of the release of theCompound 1 freebase or a pharmaceutically acceptable salt thereof or thesolid state form of Compound 1, wherein the dosage form sustains releaseof the Compound 1 freebase or a pharmaceutically acceptable salt thereofor the solid state form of Compound 1 for from about 4 to about 24 hoursfollowing entry of the dosage form into a use environment, wherein thedosage form has a release rate of not more than about 60% after passageof about 4 hours following said entry into said use environment. In oneembodiment, the dosage form comprises about 7.5 mg or about 15 mg orabout 30 mg or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of a solid state form of Compound 1. In one embodiment, thesolid state form is Freebase Hydrate Form B. In one embodiment, thesolid state form is Freebase Hydrate Form C. In one embodiment, thesolid state form is Freebase Anhydrate Form D. In one embodiment, thesolid state form is Tartrate Hydrate. In one embodiment, the dosage formfurther has a release rate of from about 50% to about 80% after passageof about 8 hours following entry of the dosage form into a useenvironment, from about 55% to about 90% after passage of about 10 hoursfollowing entry of the dosage form into a use environment, and/or fromabout 70% to 1000% after passage of about 20 hours following entry ofthe dosage form into a use environment.

In another aspect, the disclosure is directed to an extended releasesolid oral dosage form comprising Compound 1 freebase or apharmaceutically acceptable salt thereof or a solid state form ofCompound 1 for use in reducing signs and symptoms associated withrheumatoid arthritis in an adult subject, the use comprising once dailyadministration to the subject, particularly a subject suffering from orsusceptible to rheumatoid arthritis, of the extended release solid oraldosage form, wherein the solid dosage form comprises about 7.5 mg orabout 15 mg or about 30 mg or about 45 mg, per unit dosage form (e.g.,per tablet or capsule) of Compound 1 freebase, or a pharmaceuticallyacceptable salt thereof or a solid state form of Compound 1 in an amountsufficient to deliver to the subject about 7.5 mg, or about 15 mg, orabout 30 mg, or about 45 mg, per unit dosage form (e.g., per tablet orcapsule), of Compound 1 freebase equivalent, and a pharmaceuticallyacceptable polymeric carrier substantially contributing to themodification of the release of the Compound 1 freebase or apharmaceutically acceptable salt thereof or the solid state form ofCompound 1, wherein the dosage form sustains release of the Compound 1freebase or a pharmaceutically acceptable salt thereof or the solidstate form of Compound 1 for from about 4 to about 24 hours followingentry of the dosage form into a use environment, wherein the dosage formhas a release rate of not more than about 60% after passage of about 4hours following said entry into said use environment. In one embodiment,the dosage form comprises about 7.5 mg or about 15 mg or about 30 mg orabout 45 mg, per unit dosage form (e.g., per tablet or capsule), of asolid state form of Compound 1. In one embodiment, the solid state formis Freebase Hydrate Form B. In one embodiment, the solid state form isFreebase Hydrate Form C. In one embodiment, the solid state form isFreebase Anhydrate Form D. In one embodiment, the solid state form isTartrate Hydrate. In one embodiment, the dosage form further has arelease rate of from about 50% to about 80% after passage of about 8hours following entry of the dosage form into a use environment, fromabout 55% to about 90% after passage of about 10 hours following entryof the dosage form into a use environment, and/or from about 70% to 100%after passage of about 20 hours following entry of the dosage form intoa use environment.

In the foregoing methods, in one embodiment, the pharmaceuticallyacceptable polymeric carrier comprises a release control polymer. In oneembodiment, the release control polymer is hydroxypropylmethylcellulose. In one embodiment, the dosage form comprises a pH modifier.In one embodiment, the pH modifier is tartaric acid. In one embodiment,the dosage form comprises from about 10 w/w % to about 35 w/w % tartaricacid. In one embodiment, the dosage form comprises about 10 w/w %tartaric acid. In one embodiment, the dosage form comprises about 20 w/w% tartaric acid. In one embodiment, the dosage form comprises about 30w/w % tartaric acid.

In another embodiment the methods of the present disclosure furthercomprise administering Compound 1 or a solid state form thereof for atleast 8 weeks. In another embodiment, the methods of the presentdisclosure comprise administering Compound 1 or a solid state formthereof for at least 12 weeks.

In another embodiment, the present disclosure relates to the use of asolid state form of Compound 1 for treating a condition as described inthe various embodiments of the present disclosure.

In another embodiment, the present disclosure relates to a solid stateform of Compound 1 for use in treatment of a condition as described inthe various embodiments of the present disclosure.

III. Combination Therapy and Fixed-Dose Combinations

The present disclosure further relates to (i) methods of treatment anduses as previously described that further comprise the administration ofone or more additional therapeutic agents (i.e., combination therapies),and (ii) pharmaceutical compositions as previously described thatfurther comprise one or more additional therapeutic agents (i.e.,fixed-dose combinations). When administered to a subject in combinationwith one or more additional therapeutic agents, the solid state form ofCompound 1 and the additional therapeutic agent(s) can be administeredas separate dosage forms or as a single dosage form comprising the solidstate form of Compound 1 and the additional therapeutic agent(s). Ifadministered as a separate dosage form, the additional therapeutic agentmay be administered either simultaneously with, or sequentially with,the dosage form comprising the solid state form of Compound 1.

For example, the solid state forms of the present disclosure may beadministered in a pharmaceutically acceptable form either alone or incombination with one or more additional agents that modulate a mammalianimmune system or with anti-inflammatory agents. These agents may includebut are not limited to cyclosporin A (e.g., SANDIMMUNE® or NEORAL®,rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin,mycophenolate (e.g., CELLCEPT®), azathioprine (e.g., IMURAN®),daclizumab (e.g., ZENAPAX®), OKT3 (e.g., ORTHOCLONE®), AtGam, aspirin,acetaminophen, aminosalicylate, ciprofloxacin, corticosteroid,metronidazole, probiotic, tacrolimus, ibuprofen, naproxen, piroxicam,and anti-inflammatory steroids (e.g., prednisolone or dexamethasone). Incertain embodiments, the one or more additional agents are selected fromthe group consisting of aspirin, acetaminophen, aminosalicylate,ciprofloxacin, corticosteroid, cyclosporine, metronidazole, probiotic,tacrolimus, ibuprofen, naproxen, piroxicam, prednisolone, dexamethasone,anti-inflammatory steroid, methotrexate, chloroquine, azathioprine,hydroxychloroquine, penicillamine, sulfasalazine, leflunomide,tocilizumab, anakinra, abatacept, certolizumab pegol, golimumab,vedolizumab, natalizumab, ustekinumab, rituximab, efalizumab, belimumab,etanercept, infliximab, adalimumab, and immune modulator (e.g.,activator) for CD4+CD25+ Treg cells.

Non-limiting examples of therapeutic agents for rheumatoid arthritiswith which a compound of the invention can be combined include thefollowing: cytokine suppressive anti-inflammatory drug(s) (CSAIDs);antibodies to or antagonists of other human cytokines or growth factors,for example, TNF, LT, IL-1, IL-2, IL-3. IL-4, IL-5, IL-6, IL-7, IL-8.IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF,and PDGF. Compounds of the invention can be combined with antibodies tocell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30,CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligandsincluding CD154 (gp39 or CD40L). Combinations of therapeutic agents mayinterfere at different points in the autoimmune and subsequentinflammatory cascade. Such examples may include TNF antagonists likechimeric, humanized or human TNF antibodies, adalimumab (such as HUMIRA™brand adalimumab), infliximab such as CA2 (REMICADE™ brand infliximab),golimumab such as SIMPONI™ (golimumab), certolizumab pegol such asCIMZIA™, tocilizumab such as ACTEMRA™, CDP 571, and soluble p55 or p75TNF receptors, derivatives, thereof, etanercept such as p75TNFR1gG(ENBREL™ brand etanercept) or p55TNFRIgG (lenercept), and also TNFαconverting enzyme (TACE) inhibitors; similarly IL-1 inhibitors(Interleukin-1-converting enzyme inhibitors, IL-1RA etc.) may beeffective for the same reason. Other combinations include Interleukin11.

The solid state form may also be combined with nonbiologic DMARDS orother agents, such as methotrexate, 6-mercaptopurine, azathioprinesulphasalazine, mesalamine, olsalazine chloroquinine/hydroxychloroquine,penicillamine aurothiomalate (intramuscular and oral), azathioprine,colchicine, corticosteroids (oral, inhaled and local injection), beta-2adrenoreceptor agonists (salbutamol, terbutaline, salmeterol), xanthines(theophylline, aminophylline), cromoglycate, nedocromil, ketotifen,ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolatemofetil, leflunomide. NSAIDs, for example, ibuprofen, corticosteroidssuch as prednisolone, phosphodiesterase inhibitors, adenosine agonists,antithrombotic agents, complement inhibitors, adrenergic agents, agentswhich interfere with signaling by proinflammatory cytokines such as IL-1(e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1p converting enzymeinhibitors, T-cell signalling inhibitors such as kinase inhibitors,metalloproteinase inhibitors, sulfasalazine, and 6-mercaptopurines. Thesolid state form may also be combined with methotrexate.

Non-limiting examples of therapeutic agents for inflammatory boweldisease (IBD) with which the solid state form can be combined mayinclude (but are not limited to) the following: budesonide; epidermalgrowth factor; corticosteroids; cyclosporin, sulfasalazine;aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole;lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide;antioxidants; thromboxane inhibitors: IL-1 receptor antagonists:anti-IL-1β monoclonal antibodies; anti-IL-6 monoclonal antibodies;growth factors; elastase inhibitors; pyridinyl-imidazole compounds,antibodies to or antagonists of other human cytokines or growth factors,for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16,IL-23, EMAP-II, GM-CSF, FGF, and PDGF: cell surface molecules such asCD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or theirligands; methotrexate; cyclosporine: FK506; rapamycin; mycophenolatemofetil: leflunomide; NSAIDs, for example, ibuprofen; corticosteroidssuch as prednisolone: phosphodiesterase inhibitors; adenosine agonists;antithrombotic agents; complement inhibitors; adrenergic agents; agentswhich interfere with signaling by proinflammatory cytokines such as TNFαor IL-1 (e.g., NIK, IKK, or MAP kinase inhibitors); IL-1β convertingenzyme inhibitors; TNFα converting enzyme inhibitors; T-cell signalinginhibitors such as kinase inhibitors; metalloproteinase inhibitors;sulfasalazine; azathioprine; 6-mercaptopurines; angiotensin convertingenzyme inhibitors; soluble cytokine receptors and derivatives thereof(e.g. soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) andanti-inflammatory cytokines (e.g., IL-4, IL-10, IL-11, IL-13 and TGFβ).The solid state form may also be combined with methotrexate.

Examples of therapeutic agents for Crohn's disease with which the solidstate form can be combined include the following: TNF antagonists, forexample, anti-TNF antibodies, adalimumab (such as HUMIRA™ brandadalimumab), infliximab such as CA2 (REMICADE™ brand infliximab),certolizumab pegol such as CIMZIA™, golimumab such as SIMPONI™,(golimumab), CDP 571, TNFR-Ig constructs, etanercept such as p75TNFRIgG(ENBREL™ brand etanercept) and lenercept such as p55TNFRIgG (Lenercept™)inhibitors and PDE4 inhibitors.

The solid state form can be combined with corticosteroids, for example,budesonide and dexamethasone; sulfasalazine, 5-aminosalicylic acid;olsalazine; and agents which interfere with synthesis or action ofproinflammatory cytokines such as IL-1, for example, IL-1β convertingenzyme inhibitors and IL-1ra; T cell signaling inhibitors, for example,tyrosine kinase inhibitors; 6-mercaptopurine: IL-11; mesalamine;prednisone; azathioprine; mercaptopurine; methylprednisolone sodiumsuccinate; diphenoxylate/atrop sulfate: loperamide hydrochloride;methotrexate: omeprazole; folate: ciprofloxacin/dextrose-water:hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide;metronidazole: thimerosal/boric acid; cholestyramine/sucrose;ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidinehydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen;promethazine hydrochloride: sodium phosphate;sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphenenapsylate; hydrocortisone; multivitamins; balsalazide disodium; codeinephosphate/apap: colesevelam HCl; cyanocobalamin; folic acid;levofloxacin; methylprednisolone; natalizumab and interferon-gamma.

Non-limiting examples of therapeutic agents for multiple sclerosis (MS)with which the solid state form can be combined include the following:corticosteroids; prednisolone; methylprednisolone; azathioprine;cyclophosphamide: cyclosporine: methotrexate: 4-aminopyridine;tizanidine; interferon-β1a (AVONEX®: Biogen): interferon-β1b(BETASERON®: Chiron/Berlex); interferon α-n3) (InterferonSciences/Fujimoto), interferon-α (Alfa Wassermann/J&J), interferonβ1A-1F (Serono/Inhale Therapeutics), Peginterferon α 2b(Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; TevaPharmaceutical Industries, Inc.); hyperbaric oxygen; intravenousimmunoglobulin; cladribine; antibodies to or antagonists of other humancytokines or growth factors and their receptors, for example, TNF, LT,IL-1, IL-2, IL-6. IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II,GM-CSF, FGF, and PDGF. A compound of the invention can be combined withantibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19,CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or theirligands. The solid state form may also be combined with agents such asmethotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil,leflunomide, an S1P1 agonist, NSAIDs, for example, ibuprofen,corticosteroids such as prednisolone, phosphodiesterase inhibitors,adenosineagonists, antithrombotic agents, complement inhibitors,adrenergic agents, agents which interfere with signaling byproinflammatory cytokines such as TNFα or IL-1 (e.g., NIK, IKK, p38 orMAP kinase inhibitors), IL-1β converting enzyme inhibitors, TACEinhibitors, T-cell signaling inhibitors such as kinase inhibitors,metalloproteinase inhibitors, sulfasalazine, azathioprine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g., soluble p55 or p75 TNFreceptors, sIL-1RI, sIL-1 RII, sIL-6R) and anti-inflammatory cytokines(e.g. IL-4, IL-10, IL-13 and TGFβ). Examples of therapeutic agents formultiple sclerosis in which a compound of the invention can be combinedto include interferon-β, for example, IFNβ1a and IFNβ1b; copaxone,corticosteroids, caspase inhibitors, for example inhibitors ofcaspase-1, IL-1 inhibitors, TNF inhibitors, and antibodies to CD40ligand and CD80.

The solid state form may also be combined with agents, such asalemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliprodenhydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol,α-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptorantagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulatedmitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidoneallotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2,tiplimotide, VLA-4 antagonists (for example, TR-14035, VLA4 Ultrahaler,Antegran-ELAN/Biogen), interferon gamma antagonists and IL-4 agonists.

Non-limiting examples of therapeutic agents for ankylosing spondylitis(AS) with which the solid state form can be combined include thefollowing: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam,indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine,methotrexate, azathioprine, minocyclin, prednisone, and anti-TNFantibodies, adalimumab (such as HUMIRA™ brand adalimumab), infliximabsuch as CA2 (REMICADE™ brand infliximab), CDP 571, TNFR-Ig constructs,etanercept such as p75TNFRIgG (ENBREL™ brand etanercept) and lenerceptsuch as p55TNFRIgG (LENERCEPT™).

Non-limiting examples of therapeutic agents for psoriasis (Ps, such asmoderate to severe plaque psoriasis) with which the solid state form canbe combined include the following: calcipotriene, clobetasol propionate,triamcinolone acetonide, halobetasol propionate, tazarotene,methotrexate, fluocinonide, betamethasone diprop augmented, fluocinoloneacetonide, acitretin, tar shampoo, betamethasone valerate, mometasonefuroate, ketoconazole, pramoxine/fluocinolone, hydrocortisone valerate,flurandrenolide, urea, betamethasone, clobetasol propionate/emoll,fluticasone propionate, azithromycin, hydrocortisone, moisturizingformula, folic acid, desonide, pimecrolimus, coal tar, diflorasonediacetate, etanercept folate, lactic acid, methoxsalen, hc/bismuthsubgal/znox/resor, methylprednisolone acetate, prednisone, sunscreen,halcinonide, salicylic acid, anthralin, clocortolone pivalate, coalextract, coal tar/salicylic acid, coal tar/salicylic acid/sulfur,desoximetasone, diazepam, emollient, fluocinonide/emollient, mineraloil/castor oil/na lact, mineral oil/peanut oil, petroleum/isopropylmyristate, psoralen, salicylic acid, soap/tribromsalan, thimerosal/boricacid, celecoxib, infliximab, cyclosporine, alefacept, efalizumab,tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874,ustekinumab, and adalimumab (such as HUMIRA™ brand adalimumab).

Non-limiting examples of therapeutic agents for psoriatic arthritis(PsA) with which the solid state form can be combined include thefollowing: methotrexate, etanercept, rofecoxib, celecoxib, folic acid,sulfasalazine, naproxen, leflunomide, methylprednisolone acetate,indomethacin, hydroxychloroquine sulfate, prednisone, sulindac,betamethasone diprop augmented, infliximab, methotrexate, folate,triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam,diclofenac sodium, ketoprofen, meloxicam, methylprednisolone,nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenacsodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodiumthiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium,sulfadiazine, thioguanine, valdecoxib, alefacept, adalimumab (such asHUMIRA™ brand adalimumab), and efalizumab.

Examples of therapeutic agents for SLE (Lupus) with which the solidstate form can be combined include the following: NSAIDS, for example,diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2inhibitors, for example, celecoxib, rofecoxib, valdecoxib;anti-malarials, for example, hydroxychloroquine; steroids, for example,prednisone, prednisolone, budesonide, dexamethasone; cytotoxics, forexample, azathioprine, cyclophosphamide, mycophenolate mofetil,methotrexate; inhibitors of PDE4 or purine synthesis inhibitor, forexample CELLCEPT®. The solid state form may also be combined with agentssuch as sulfasalazine, 5-aminosalicylic acid, olsalazine, IMURAN® andagents which interfere with synthesis, production or action ofproinflammatory cytokines such as IL-1, for example, caspase inhibitorslike IL-1β converting enzyme inhibitors and IL-1ra. The solid state formmay also be used with T cell signaling inhibitors, for example, tyrosinekinase inhibitors; or molecules that target T cell activation molecules,for example, CTLA-4-IgG or anti-B7 family antibodies, anti-PD-1 familyantibodies. The solid state form can be combined with IL-11 oranti-cytokine antibodies, for example, fontolizumab (anti-IFNgantibody), or anti-receptor receptor antibodies, for example, anti-IL-6receptor antibody and antibodies to B-cell surface molecules. The solidstate form may also be used with UP 394 (abetimus), agents that depleteor inactivate B-cells, for example, Rituximab (anti-CD20 antibody),lymphostat-B (anti-BlyS antibody), TNF antagonists, for example,anti-TNF antibodies, adalimumab (such as HUMIRA™ brand adalimumab),infliximab such as CA2 (REMICADE™ brand infliximab), CDP 571, TNFR-Igconstructs, etanercept such as p75TNFRIgG (ENBREL™ brand etanercept) andlenercept such as p55TNFRIgG (LENERCEPT™).

The solid state form may also be combined with an immune modulator forCD4+CD25+ Treg cells. Treg cells are essential for maintaining normalimmune homeostasis. In patients with autoimmune diseases, reducednumbers or functional impairment of Treg cells has been observed,leading to loss of this finely-tuned mechanism. A humanized agonisticmonoclonal antibody, BT-061, binds to a unique epitope of human CD4, andinduces Treg-specific signaling events that lead to their functionalactivation. Pre-clinical data using isolated Treg cells and rheumatoidarthritis synovial fluid indicate that BT-061 leads to suppression ofCD4+ and CD8+T effector cell proliferation, reduction of the expressionof pro-inflammatory cytokines, and increase in the production of theanti-inflammatory cytokine TGFβ. Thus similar immune modulators forCD4+CD25+ Treg cells can also be co-administered with a compound of theinvention for treating any of the inflammatory disease/disorder, or anautoimmune disease/disorder described herein, including but not limitedto rheumatoid arthritis, Crohn's disease, ankylosing spondylitis,psoriatic arthritis, psoriasis, ulcerative colitis, systemic lupuserythematosus, lupus nephritis, diabetic nephropathy, dry eye syndrome,Sjogren's syndrome, alopecia areata, vitiligo, or atopic dermatitis. Incertain embodiments, the combination treats rheumatoid arthritis,Crohn's disease, psoriasis, or psoriatic arthritis, including moderatelyto severely active rheumatoid arthritis, Crohn's disease, psoriasis, orpsoriatic arthritis. In certain embodiments, the rheumatoid arthritis,Crohn's disease, psoriasis, or psoriatic arthritis patient being treatedhas inadequately responded to or has discontinued therapy due to loss ofresponse to or intolerance to a first line therapy (such as a DMARD,including methotrexate) or an anti-TNF, therapy.

In certain embodiments, the immune modulator has one or more (or all) ofthe following properties: (1) activates a subset of CD4+ T cellscomprising CD4+CD25+ regulatory T cells (Treg), or CD4+CD25+ Treg cells;(2) binds only to a special epitope of the human CD4 antigen (such asthe IgG-like C2 type 1 domain of CD4), which said epitope of human CD4may be bound by a mouse IgG1 anti-CD4 monoclonal antibody B-F5 or ahumanized version thereof, such as the BT-061 hB-F5 antibodytregalizumab as described in U.S. Pat. No. 7,452,981 (incorporatedherein by reference, including all sequences of the VH and VL chainsdisclosed therein): (3) provides an activation signal to naturallyoccurring Treg cells but does not activate conventional T cells (e.g.,CD4+ T cells that are not activated in (1). CD8+ cytotoxic T cells,etc.); and (4) is not a depleting anti-CD4 antibody that depletes CD4+ Tcells, and/or does not appreciably trigger ADCC or CDC.

VI. Pharmaceutical Compositions

The present disclosure further relates, in part, to compositionscomprising Compound 1 or a pharmaceutically acceptable salt thereof, orone or more solid state forms of Compound 1. Although the solid stateform may be administered alone or in the form of a pharmaceuticalcomposition, administration generally will be in the form of apharmaceutical composition. In some embodiments, the compositioncomprises Compound 1 or a pharmaceutically acceptable salt thereof or asolid state form of Compound 1 in association with a pharmaceuticallyacceptable carrier. The preferred composition depends on the method ofadministration, and typically comprises one or more conventionalpharmaceutically acceptable carriers, adjuvants, and/or vehicles(together referred to as “excipients”). Such compositions can beformulated for various routes of systemic or local delivery for example,by oral administration, topical administration, transmucosaladministration, rectal administration, intravaginal administration, oradministration by subcutaneous, intrathecal, intravenous, intramuscular,intraperitoneal, intranasal, intraocular or intraventricular injection.

Solid dosage forms for oral administration include, for example,capsules, tablets, pills, powders, and granules. In such solid dosageforms, the compounds or salts are ordinarily combined with one or moreexcipients. If administered per os, the compounds or salts can be mixedwith, for example, lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets cancontain a controlled-release formulation, as can be provided in, forexample, a dispersion of the compound or salt in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage formsalso can comprise pH modifiers, such as sodium citrate; magnesium orcalcium carbonate or bicarbonate; tartaric acid, fumaric acid, citricacid, succinic acid, malic acid, and phosphoric acid and combinationsthereof. Tablets and pills additionally can be prepared with entericcoatings.

In one embodiment, the pharmaceutical composition is a tablet dosageform. In one aspect, the tablet is coated with a pharmaceuticallyacceptable polymer.

In one embodiment, tablet is a controlled-release formulation, such asan extended release tablet dosage form (also referred to herein as amodified release or sustained release formulation). Such formulationspermit the sustained release of the active ingredient over an extendedperiod of time, as compared to immediate release solid dosage forms,which permit the release of most or all of the active ingredient over ashort period of time (e.g., typically around 60 minutes or less). In oneaspect, the tablet comprises an active ingredient and at least oneadditive selected from the group consisting of a release controlpolymer, a filler, a glidant, a lubricant (e.g., for use in compactingthe granules), a pH modifier, a surfactant, and combinations thereof. Inone aspect, the tablet comprises an active ingredient, a release controlpolymer, a filler, a glidant, and a lubricant. In one aspect, the tabletcomprises an active ingredient, a release control polymer, a filler, aglidant, a lubricant, and a pH modifier.

In certain embodiments, the release control polymer will be ahydrophilic polymer. Examples of suitable release control polymersinclude, but are not limited to a cellulose derivative with a viscosityof between 1000 and 150,000 mPA-s, hydroxypropylmethyl cellulose (e.g.,Hypromellose 2208 or controlled release grades of hydroxypropylmethylcellulose, including the E, F, and K series), copolymers of acrylic acidcrosslinked with a polyalkenyl polyether (e.g., Carbopol® polymers),hydroxypropyl cellulose, hydroxyethyl cellulose, non-ionic homopolymersof ethylene oxide (e.g., Polyox™), water soluble natural gums ofpolysaccharides (e.g., xanthan gum, alginate, locust bean gum, etc.),crosslinked starch, polyvinyl acetates, polyvinylpyrrolidone, mixturesof polyvinyl acetates and polyvinyl pyrrolidone, and combinationsthereof. In one embodiment, the release control polymer is selected fromthe group consisting of hydroxypropylmethyl cellulose, copolymers ofacrylic acid crosslinked with a polyalkenyl polyether (e.g., Carbopol®polymers), and combinations thereof. Examples of suitable fillers(“bulking agents”) include, but are not limited to, microcrystallinecellulose (e.g., Avicel® PH 101; Avicel® PH 102), mannitol (e.g.,Pearlitol® 100 SD or Pearlitol® 200 SD), lactose, sucrose, sorbitol, andthe like. In one embodiment, the filler is selected from the groupconsisting of microcrystalline cellulose, mannitol, and combinationsthereof. Examples of suitable glidants include, but are not limited to,silicone dioxide (e.g., colloidal silicon dioxide), calcium silicate,magnesium silicate, talc, and combinations thereof. In one embodiment,the glidant is colloidal silicone dioxide. Examples of suitablelubricants include, but are not limited to, polyethylene glycol (e.g.,having a molecular weight of from 1000 to 6000), magnesium stearate,calcium stearate, sodium stearyl fumarate, talc, and the like. In oneembodiment, the lubricant is magnesium stearate. Examples of suitable pHmodifiers include, but are not limited to, organic acids, such astartaric acid, citric acid, succinic acid, fumaric acid; sodium citrate;magnesium or calcium carbonate or bicarbonate; and combinations thereof.In one embodiment, the pH modifier is tartaric acid. Examples ofsuitable surfactants include sodium lauryl sulfate.

In one embodiment, the pharmaceutical composition comprises from about10 w/w % to about 35 w/w % of a pH modifier, and in particular, tartaricacid, fumaric acid, citric acid, succinic acid, malic acid, orcombinations thereof. In other embodiments, the formulation comprisesfrom about 20 w/w % to about 35 w/w %, or from about 20 w/w % to about30 w/w %, or from about 20 w/w % to about 25 w/w %, or about 10 w/w %,about 15 w/w %, about 20 w/w %, about 25 w/w % or about 30 w/w % pHmodifier. In one embodiment, the pH modifier is tartaric acid.

IV. Pharmacokinetic Parameters

15 mg Dosage Formulations

In certain embodiments, the methods of the present disclosure compriseadministering to an adult subject (e.g., a human subject) Compound 1(freebase), or a pharmaceutically acceptable salt thereof, or acrystalline hydrate of Compound 1 in an amount sufficient to deliver tothe subject 15 mg of Compound 1 freebase equivalent. In one embodiment,the freebase or the hydrate is in a once daily extended releaseformulation.

Unless otherwise indicated, the following pharmacokinetic parameters areachieved after administration of a single 15 mg dose the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate (e.g., Freebase Hydrate Form C) to the adultsubject, or after administration of a sufficient number of once-daily 15mg doses to achieve a steady-state. By a single 15 mg dose, it is meanta single dosage unit containing an amount of freebase orpharmaceutically acceptable salt or crystalline hydrate sufficient todeliver to the subject 15 mg of Compound 1 freebase equivalent. In oneembodiment, the single dosage unit is a once daily extended releaseformulation.

30 mg Dosage Formulations

In certain embodiments, the methods of the present disclosure compriseadministering to an adult subject (e.g., a human subject) 30 mg ofCompound 1 (freebase), or a pharmaceutically acceptable salt thereof ora crystalline hydrate of Compound 1 in an amount sufficient to deliverto the subject 30 mg of Compound 1 freebase equivalent. In oneembodiment, the freebase or the hydrate is in a once daily extendedrelease formulation.

Unless otherwise indicated, the following pharmacokinetic parameters areachieved after administration of a single 30 mg dose the Compound 1(freebase) or a pharmaceutically acceptable salt thereof or thecrystalline hydrate (e.g., Freebase Hydrate Form C) to the adultsubject, or after administration of a sufficient number of once-daily 30mg doses to achieve a steady-state. By a single 30 mg dose, it is meanta single dosage unit containing an amount of freebase orpharmaceutically acceptable salt or crystalline hydrate sufficient todeliver to the subject 30 mg of Compound 1 freebase equivalent. In oneembodiment, the single dosage unit is a once daily extended releaseformulation.

VIII. Extended Release Tablets

In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate used in the methodsof the present disclosure is in a once daily extended releaseformulation. In one embodiment, the Compound 1 (freebase) or apharmaceutically acceptable salt thereof or the crystalline hydrate isin a once daily extended release formulation, and the formulationdelivers about 7.5 mg or about 15 mg or about 30 mg or about 45 mg perunit dosage form (e.g., per tablet or capsule) of Compound 1 (freebaseequivalent) orally QD (once daily). In one particular embodiment, thecrystalline hydrate is Freebase Hydrate Form C.

In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate is in a once dailyextended release formulation, and the formulation delivers 7.5 mg ofCompound 1 (freebase equivalent) orally QD (once daily). In some suchembodiments, the once daily extended release formulation will have arelative bioavailability approximately equivalent to that of animmediate release capsule comprising Compound 1 (freebase) or apharmaceutically acceptable salt thereof or a solid state form thereofthat delivers 3 mg of Compound 1 (freebase equivalent) and that isadministered two times per day (BID). In one embodiment, the immediaterelease capsule comprises a crystalline hydrate of Compound 1. In oneembodiment, the immediate release capsule comprises Freebase HydrateForm C. In one embodiment, the immediate release capsule comprisesTartrate Hydrate.

In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate is in a once dailyextended release formulation, and the formulation delivers 15 mg ofCompound 1 (freebase equivalent) orally QD (once daily). In some suchembodiments, the once daily extended release formulation will have arelative bioavailability approximately equivalent to that of animmediate release capsule comprising Compound 1 (freebase) or apharmaceutically acceptable salt thereof or a solid state form thereofthat delivers 6 mg of Compound 1 (freebase equivalent) and that isadministered two times per day (BID). In one embodiment, the immediaterelease capsule comprises a crystalline hydrate of Compound 1. In oneembodiment, the immediate release capsule comprises Freebase HydrateForm C. In one embodiment, the immediate release capsule comprisesTartrate Hydrate.

In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate is in a once dailyextended release formulation, and the formulation delivers 30 mg ofCompound 1 (freebase equivalent) orally QD (once daily). In some suchembodiments, the once daily extended release formulation will have arelative bioavailability approximately equivalent to that of animmediate release capsule comprising Compound 1 (freebase) or apharmaceutically acceptable salt thereof or a solid state form thereofthat delivers 12 mg of Compound 1 (freebase equivalent) and that isadministered two times per day (BID). In one embodiment, the immediaterelease capsule comprises a crystalline hydrate of Compound 1. In oneembodiment, the immediate release capsule comprises Freebase HydrateForm C. In one embodiment, the immediate release capsule comprisesTartrate Hydrate.

In one embodiment, the Compound 1 (freebase) or a pharmaceuticallyacceptable salt thereof or the crystalline hydrate is in a once dailyextended release formulation, and the formulation delivers 45 mg ofCompound 1 (freebase equivalent) orally QD (once daily). In some suchembodiments, the once daily extended release formulation will have arelative bioavailability approximately equivalent to that of animmediate release capsule comprising Compound 1 (freebase) or apharmaceutically acceptable salt thereof or a solid state form thereofthat delivers 18 mg of Compound 1 (freebase equivalent) and that isadministered two times per day (BID). In one embodiment, the immediaterelease capsule comprises a crystalline hydrate of Compound 1. In oneembodiment, the immediate release capsule comprises Freebase HydrateForm C. In one embodiment, the immediate release capsule comprisesTartrate Hydrate.

V. Ankylosing Spondylitis

Ankylosing Spondylitis (AS) is a chronic, inflammatory rheumatic diseaseprimarily affecting the axial skeleton, characterized by chronic backpain (including nocturnal back pain), morning stiffness, enthesitis,peripheral arthritis, and extra-articular manifestations. The “early”form of this disease (non-radiographic axial spondyloarthritis(nr-axSpA)) shares many of AS disease characteristics.

Due to the longstanding debilitating nature of AS, irreversiblestructural damage often occurs, negatively impacting patients' lives. Nocure for AS exists, thus the primary goal of treatment is to maximizepatients' quality of life through controlling the signs and symptoms ofdisease, preventing structural damage, and maintaining physicalfunction, ideally by achieving sustained clinical remission or, atminimum, low disease activity. Nonsteroidal anti-inflammatory drugs(NSAIDs) are the first-line treatment for AS, followed by biologicdisease-modifying antirheumatic drugs (bDMARDs), such as tumor necrosisfactor (TNF) inhibitors or interleukin-17 (IL-17) inhibitors, inpatients who do not sufficiently respond to NSAIDs. TNF inhibitors andIL-17 inhibitors are efficacious in some patients with AS, but there arestill patients for whom neither of these approved therapies addressindividual treatment goals. AS is a difficult disease to treat, as shownbased on low efficacy achieved with IL-6 inhibitors tocilizumab andsarilumab, as well as IL-12/23 inhibitor ustekinumab and T cell blockadeinhibitor abatacept. See, e.g., Sieper et al., Ann. Rheum. Dis. 201473:95-100. Sieper et al., Ann. Rheum. Dis. 2015 74:1051-1057; Deodhar etal., Arthritis and Rheumatology 2019 71:258-270, and Song et al., Ann.Rheum. Dis. 2011 70:1108-1110.

The JAK family is composed of 4 members: JAK1, 2, 3, and tyrosine kinase2 (Tyk2). These cytoplasmic tyrosine kinases act in tandem to activatethe Signal Transducer and Activator of Transcription (STAT) thattransduce cytokine-mediated signals and are associated with multiplemembrane cytokine receptors such as common gamma-chain (CGC) receptorsand the glycoprotein 130 trans-membrane proteins. JAK3 and JAK1 arecomponents of the CGC cytokine receptor complexes that are responsiblefor the signaling of the inflammatory cytokines IL-2, -4, -7, -9, -15and -21; whereas IL-12 and IL-23 signal through JAK2 and Tyk2. SeeGhoreschi, et al., Immunol Rev. (2009), 228:273-87. Propagation of thesesignals is important in the amplification of inflammatory responses inaxial spondyloarthritis (axSpA). Upadacitinib, a JAK inhibitorengineered for increased selectivity for JAK1 over JAK2, JAK3, andtyrosine kinase 2, has been investigated for the treatment ofbDMARD-naïve patients with AS who had an inadequate response tonon-steroidal anti-inflammatory drugs (NSAIDs) in the randomized,placebo-controlled phase 2/3 SELECT-AXIS 1 study. See Example 2, herein.A second study (SELECT-AXIS-2) is underway, expanding the scope ofenrollment to non-radiographic axial spondyloarthritis (nr-axSpA)patients and AS bDMARD-IR patients. See Example 3.

The SELECT-AXIS 1 met its primary endpoint of significantly greaterachievement of Assessment of SpondyloArthritis International Society(ASAS40) response at Week 14, as well as several disease activitymeasures (ASDAS, BASDAI, ASAS, and their components), inflammation(based on MRI of spine and sacroiliac joints as well as hsCRP), physicalfunction (BASFI), quality of life (ASQoL, ASAS HI), and other aspects ofdisease (BASMI, MASES), reflecting significant improvement in outcomesfor upadacitinib versus placebo. Furthermore, a review of the placebocorrected data for upadacitinib at Week 14, biologics Ixekizumab andAdalimumab at Week 16, and JAK small molecule inhibitors Tofacitinib andFilgotinib at Week 12 for key primary and secondary endpoints, while nota head to head comparison, suggests that upadacitinib 15 mg QD showsdecided promise for the more difficult to achieve endpoints ASAS PR,ASDAS ID, and ASDAS LDA versus the other two JAK small moleculeinhibitors, with a remarkable efficacy only comparable to thatdemonstrated with the biologics. See Example 2, and van der Heijde etal. Lancet (2018) 392: 2441-2451, van der Heijde D. et al. Ann. Rheum.Dis. (2017) 1-8; van der Heijde et al. Lancet (2018) 2378-2387.Furthermore, this efficacy, once achieved at Week 14, was sustained orimproved over time, with long term efficacy in these difficult toachieve endpoints (including ASDAS major improvement (MI) and ASDASclinically important improvement (CII)), sustained or improved up to andincluding Week 64. In patients who switched from placebo to upadacitinibat Week 14, a similar speed of onset and magnitude of efficacy responsewas observed up to and including Week 64 compared with those whoreceived continuous upadacitinib starting at Week 0. Based on theresults of phase 2/3 study SELECT-AXIS 1 and the consistent safety datafrom other upadacitinib clinical trials, the benefit-risk profile ofupadacitinib in AS (particularly compared to the risk profile of othersmall molecule JAK inhibitors), and viewed in the context of thebenefit-risk of TNF inhibitors and IL-17 inhibitors, presents apromising oral targeted treatment option for patients with AS,especially for those AS (as well as nr-axSpA patients) who have activedisease and inadequate response to NSAIDs.

VI. Psoriatic Arthritis

Psoriatic arthritis (PsA) is a systemic inflammatory disease withheterogeneous clinical manifestations such as plaque psoriasis,arthritis, dactylitis, and enthesitis, and is interrelated with AS, asit shares genetic and clinical features (e.g., axial involvement withback pain, peripheral arthritis or enthesitis, genetic association withHLA-B27 as well as presence of extra-articular manifestations). Multiplecytokines such as IL-1, -6, -12, -17, -20, and -23 are thought to beinvolved in the activation and proliferation of epidermal keratinocytesin psoriatic lesions. See e.g., Nestle, et al., N. Engl. J. Med. (2009)361:496-509. The IL-17/IL-23 cytokine axis is also thought to beimportant in PsA pathogenesis. See e.g., Mease, Curr. Opin. Rheumatol.(2015) 27:127-33. Thus, blockade of JAK1 could inhibit the response ofcentral cytokine signals thought to be important in the pathogenesis ofPsA. Current treatment guidelines for PsA vary, recommendingconventional synthetic disease-modifying anti-rheumatic drugs (DMARDs)such as methotrexate as initial therapy, followed by biologic DMARDs ortargeted synthetic DMARDs, such as tofacitinib, or TNFi initially,followed by other approved therapies. While multiple therapeutic choicesare available, additional options are needed in order to reach the moredifficult to achieve endpoints, such as achievement of minimal diseaseactivity (MDA), as well as treatment of the psoriasis as a skinmanifestation of PsA, with achievement of PASI 75 or PASI 90. The JAK1inhibitor upadacitinib has been investigated for the treatment ofpatients with active Psoriatic Arthritis and a previous inadequateresponse to at least one non-biologic Disease Modifying Anti-RheumaticDrug (non-biologic DMARD) (SELECT PSA1) or previous inadequate responseto at least one biologic Disease Modifying Anti-Rheumatic Drug (bDMARD)(SELECT PSA2). See Examples 4 and 5. In these two trials, greaterefficacy was demonstrated for once daily upadacitinib 15 mg and 30 mgversus placebo for clinical manifestations of psoriatic arthritisincluding musculoskeletal symptoms (peripheral arthritis, enthesitis,dactylitis, and spondylitis), psoriasis, physical function, pain,fatigue, and quality of life. Efficacy was observed as early as week 2.Furthermore, a review of the placebo corrected data for upadacitinib andthe JAK small molecule inhibitor Tofacitinib (approved for the lower (5mg BID) dose in the treatment of PsA) for key primary and secondaryendpoints, while not a head to head comparison, suggests thatupadacitinib 15 mg QD and 30 mg QD shows decided promise for the moredifficult to achieve endpoints of minimal disease activity (MDA), aswell as psoriasis endpoints PASI 75 or PASI 90, as well as certain ACRcomponents (e.g., ACR20/50/70). See Examples 4 and 5, as well as Gladmanet al., New England Journal of Medicine (2017) 377:1525-1536 and Mease Pet. al., N Engl J Med (2017) 377:1537-1550. Furthermore, it was observedthat this efficacy, once achieved, was sustained or improved over timeduring the course of the daily treatment.

Thus, in one aspect, provided is a method for treating variousspondyloarthritic and psoriatic conditions, including types of axialspondyloarthritis (axSpA), psoriatic arthritis (PsA), and psoriasis(PsO) by administering the JAK1 inhibitor, upadacitinib free base or apharmaceutically acceptable salt, to a subject in need thereof. Invarious aspects, provided is a method for treating activenon-radiographic axSpA (nr-axSpA), methods for treating activeankylosing spondylitis (AS), and methods for treating active psoriaticarthritis (PsA) and active psoriasis (PsO), including PsO as a skinmanifestation of PsA.

In one embodiment, the JAK1 inhibitor useful in the methods disclosedherein is upadacitinib freebase. Upadacitinib freebase solid state formsinclude amorphous upadacitinib freebase and crystalline freebases ofupadacitinib. Crystalline freebases of upadacitinib include thoseselected from the group consisting of crystalline freebase solvates ofupadacitinib, crystalline freebase hydrates of upadacitinib (e.g.,crystalline freebase hemihydrates of upadacitinib), and crystallinefreebase anhydrates of upadacitinib. In one embodiment, the crystallinefreebase of upadacitinib is a crystalline freebase hemihydrate ofupadacitinib. In one embodiment, the crystalline freebase ofupadacitinib is Upadacitinib Freebase Hydrate Form C (which is ahemihydrate) as described in WO 2018/165581 and WO 2017/066775. Otherspecific examples of solid state forms of the JAK1 inhibitor suitablefor use in the methods disclosed herein include those selected from thegroup consisting of Amorphous Upadacitinib Freebase, UpadacitinibFreebase Solvate Form A, Upadacitinib Freebase Hydrate Form B,Upadacitinib Freebase Anhydrate Form D, and Upadacitinib TartrateHydrate, each as described in WO 2018/165581 and WO 2017/066775.

VII. Methods of Treating Axial Spondyloarthritis

Provided herein are methods of treating axial spondyloarthritis (axSpA).In a particular aspect, provided are methods of treating active axSpA,which encompasses treating subjects with active ankylosing spondylitis(AS) and active non-radiographic axial spondyloarthritis (nr-axSpA),comprising administering orally once a day a dose of the JAK1 inhibitor,upadacitinib freebase, or a pharmaceutically acceptable salt thereof, toa subject in need thereof in certain amounts and/or at certainintervals. In one aspect, the JAK1 inhibitor is upadacitinib freebase.In one aspect, the JAK1 inhibitor is administered orally once a day inan amount sufficient to deliver 15 mg of upadacitinib freebaseequivalent. In one aspect, the JAK1 inhibitor is administered orallyonce a day for at least 14 weeks. In one aspect, the JAK1 inhibitor isadministered orally once a day for at least 52 weeks.

Disease activity/severity for axSpA may be measured using a variety ofindexes, including the Assessment of SpondyloArthritis InternationalSociety (ASAS) responses (e.g., ASAS20, ASAS40, ASAS partial remission(PR). ASAS5/6); the Ankylosing Spondylitis Disease Activity Score(ASDAS), ASDAS low disease activity (LDA), ASDAS inactive disease (ID),ASDAS major improvement (MI), ASDAS clinically important improvement(CII), the magnetic resonance imaging (MRI) Spondyloarthritis ResearchConsortium of Canada (SPARCC) score for spine (MRI-Spine SPARCC): theMRI SPARCC score for sacroiliac (SI) joints (MRI-SI joints SPARCC); theBath Ankylosing Spondylitis Disease Activity Index (BASDAI); a BASDAI 50(BASDAI50) response; the Bath Ankylosing Spondylitis Functional Index(BASFI); the Ankylosing Spondylitis Quality of Life Questionnaire(ASQoL); the ASAS Health Index (HI); the Maastricht AnkylosingSpondylitis Enthesitis Score (MASES) (enthesitis); the Linear BathAnkylosing Spondylitis Metrology Index (BASMIlin) (mobility); the WorkProductivity and Activity Impairment Questionnaire-AxialSpondyloarthritis (WPAI-Axial SpA); high-sensitivity C-reactive proteinlevels (hsCRP): the Functional Assessment of Chronic IllnessTherapy-Fatigue (FACIT-F) Questionnaire: the Insomnia Severity Index(ISI); the Modified Stroke Ankylosing Spondylitis Spine Score (mSASSS);the Patient's Assessment of Total Back Pain (Total Back Pain score); thePatient's Assessment of Nocturnal Back Pain (Nocturnal Back Pain): thePatient's Global Assessment of Pain (Pt Pain); the Physician's GlobalAssessment of Disease Activity (PGA-Disease Activity): Inflammation(mean of Questions 5 and 6 of the BASDAI); Patient's Assessment of TotalBack Pain (Question 2 of BASDAI); Peripheral pain/swelling (Question 3of BASDAI); duration of morning stiffness (Question 6 of BASDAI);Patient's Global Assessment of Disease Activity (PtGA); tender jointcount (TJC68) and swollen joint count (SJC66); resolution of dactylitis;total dactylitis count; EuroQoL-5D-5L (EQ-5D-5L) Questionnaire: 36-ItemShort Form Health Survey (SF-36); Physical Activity Assessment, andNSAID score. These indexes are described in detail in the ClinicalEndpoint Definitions and Examples.

In one aspect, provided is a method of treating axSpA, including activeaxSpA, comprising administering a dose of the JAK1 inhibitor to asubject in need thereof in certain amounts and/or at certain intervalsas described herein, wherein the subject achieves an Assessment ofSpondyloArthritis International Society 40 (ASAS40) response followingadministration of the JAK1 inhibitor. In one aspect, the JAK1 inhibitoris upadacitinib freebase. In one aspect, the JAK1 inhibitor isadministered in an amount sufficient to deliver 15 mg of upadacitinibfreebase equivalent. In one aspect, the JAK1 inhibitor is administeredorally once a day for at least 14 weeks. In one aspect, the JAK1inhibitor is administered orally once a day for at least 52 weeks.

In one aspect, the subject achieves an ASAS40 response within 14 weeksof administration of the first dose of the JAK1 inhibitor (including atweek 14). In one aspect, the subject achieves an ASAS40 response within14 weeks of administration of the first dose of the JAK1 inhibitor(including at week 14), and the response is maintained or improved afterweek 14 by continuing to administer the daily dose. In one aspect, thesubject achieves an ASAS40 response within 2 weeks of administration ofthe first dose of the JAK1 inhibitor (including at week 2). In oneaspect, the subject achieves an ASAS40 response within 2 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 2), and the response is maintained or improved after week 2 bycontinuing to administer the daily dose. In one aspect, the subjectachieves an ASAS40 response within 52 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 52). In one aspect,the subject achieves an ASAS40 response within 52 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 52), and the response is maintained or improved after week 52 bycontinuing to administer the daily dose. In one aspect, the subjectachieves an ASAS40 response within 2 weeks, within 4 weeks, within 8weeks, within 12 weeks, within 14 weeks, within 18 weeks, within 24weeks, within 32 weeks, within 40 weeks, and/or within 52 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 2, week 4, week 8, week 12, week 14, week 18, week 24, week 32,week 40, and/or week 52). In one embodiment, the subject achieves anASAS40 response within 2 weeks of administration of the first dose(including at week 2) and maintains the ASAS40 response until at least14 weeks after administration of the first dose (e.g., until at leastweek 14). In one aspect, the JAK1 inhibitor is upadacitinib freebase. Inone aspect, the JAK1 inhibitor is administered in an amount sufficientto deliver 15 mg of upadacitinib freebase equivalent. In one aspect, theJAK1 inhibitor is administered orally once a day for at least 2 weeks,for at least 4 weeks, for at least 8 weeks, for at least 12 weeks, forat least 14 weeks, for at least 18 weeks, for at least 24 weeks, for atleast 32 weeks, for at least 40 weeks, and/or for at least 52 weeks. Inone embodiment, the JAK1 inhibitor is administered orally once a day forat least 14 weeks. In one aspect, the JAK1 inhibitor is administeredorally once a day for at least 52 weeks.

In another aspect, provided is a method of treating axSpA, includingactive axSpA, comprising administering the JAK1 inhibitor to a subjectin need thereof in certain amounts and/or at certain intervals asdescribed herein, wherein the subject achieves an ASAS40 response at acertain interval as described herein, and additionally achieves at leastone of the results set forth hereinafter for treatment of ankylosingspondylitis (AS) and/or non-radiographic axial spondyloarthritis(nr-axSpA) following administration of the JAK1 inhibitor. In oneaspect, the JAK1 inhibitor is upadacitinib freebase. In one aspect, theJAK1 inhibitor is administered in an amount sufficient to deliver 15 mgof upadacitinib freebase equivalent. In one aspect, the JAK1 inhibitoris administered orally once a day for at least 14 weeks. In one aspect,the JAK1 inhibitor is administered orally once a day for at least 52weeks.

In another aspect, provided is a method of treating axSpA, includingactive axSpA, in a population of subjects in need thereof, the methodcomprising administering a dose of the JAK1 inhibitor to the subjects incertain amounts and/or at certain intervals as described herein, whereina portion of subjects in the treated population achieve an ASAS40response following administration of the JAK1 inhibitor (e.g., astatistically significant population of the subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population achieve the response). In one aspect,the subjects in the treated population achieve an ASAS40 response within14 weeks of administration of the first dose of the JAK1 inhibitor(including at week 14). In one aspect, subjects in the treatedpopulation achieve an ASAS40 response within 14 weeks of administrationof the first dose of the JAK1 inhibitor (including at week 14), and theresponse is maintained or improved after week 14 by continuing toadminister a daily dose of the JAK1 inhibitor to the subjects. In oneaspect, subjects in the treated population achieve an ASAS40 responsewithin 52 weeks of administration of the first dose of the JAK1inhibitor (including at week 52). In one aspect, subjects in the treatedpopulation achieve an ASAS40 response within 52 weeks of administrationof the first dose of the JAK1 inhibitor (including at week 52), and theresponse is maintained or improved after week 52 by continuing toadminister a daily dose of the JAK1 inhibitor to the subjects. In oneaspect, the subjects in the treated population achieve an ASAS40response within 2 weeks of administration of the first dose of the JAK1inhibitor (including at week 2). In one aspect, subjects in the treatedpopulation achieve an ASAS40 response within 2 weeks of administrationof the first dose of the JAK1 inhibitor (including at week 2), and theresponse is maintained or improved after week 2 by continuing toadminister a daily dose of the JAK1 inhibitor to the subjects. In oneaspect, subjects in the treated population achieve at least one of theresults set forth hereinafter for treatment of ankylosing spondylitis(AS) and/or non-radiographic axial spondyloarthritis (nr-axSpA)following administration of the JAK1 inhibitor (e.g., a statisticallysignificant population of subjects in the treated population, and/or atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, or at least 45% of the subjects in the treatedpopulation achieve at least one of the results). In one aspect, the JAK1inhibitor is upadacitinib freebase. In one aspect, a dose of the JAK1inhibitor is administered to the population in an amount sufficient todeliver 15 mg of upadacitinib freebase equivalent. In one aspect, theJAK1 inhibitor is administered to the subjects orally once a day for atleast 14 weeks. In one aspect, the JAK1 inhibitor is administered to thesubjects orally once a day for at least 52 weeks.

Further provided are methods of reducing the signs and symptoms ofaxSpA. In one aspect, provided is a method of reducing the signs andsymptoms of axSpA, including active axSpA, comprising administering adose of the JAK1 inhibitor to a subject in need thereof in certainamounts and/or at certain intervals. In one aspect, the JAK1 inhibitoris upadacitinib freebase or a pharmaceutically acceptable salt thereof.In one aspect, the JAK1 inhibitor is administered in an amountsufficient to deliver 15 mg of upadacitinib freebase equivalent. In oneaspect, the JAK1 inhibitor is administered once a day for 14 weeks. Inone aspect, the JAK1 inhibitor is administered once a day for 52 weeks.

In one aspect, the signs and symptoms of axSpA, including active axSpA,are reduced following administration of the JAK1 inhibitor when thesubject achieves, within 14 weeks of administration of the first dose ofthe JAK1 inhibitor (including at week 14), at least one result selectedfrom the group consisting of: an ASAS40 response; a change (improvement)from baseline in ASDAS: a change (improvement) from baseline in MRISPARCC score for spine (MRI-Spine SPARCC); ASAS partial remission (PR):a BASDAI50 response; a change (improvement) from baseline in BASFI: achange (improvement) from baseline in ASQoL; a change (improvement) frombaseline in ASAS Health Index (HI); a change (improvement) from baselinein MASES (enthesitis); a change (improvement) from baseline in BASMIlin(mobility); a change (improvement) from baseline in WPAI-Axial SpA: anda change (improvement) from baseline in MRI SPARCC score for SI joints(MRI-SI joints SPARCC); or when the subject achieves, within 52 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 52), an ASAS40 response. In one aspect, the subject achieves theresponse within 14 weeks of administration of the first dose of the JAK1inhibitor (including at week 14), and the response is maintained orimproved after week 14 by continuing to administer a daily dose of theJAK1 inhibitor. In another aspect, the subject achieves the responsewithin 52 weeks of administration of the first dose of the JAK1inhibitor (including at week 52), and the response is maintained orimproved after week 52 by continuing to administer a daily dose of theJAK1 inhibitor. In one aspect, the subject achieves the response within2 weeks of administration of the first dose of the JAK1 inhibitor(including at week 2), and the response is maintained or improved afterweek 2 by continuing to administer a daily dose of the JAK1 inhibitor.

For any of the methods of treating axSpA and/or methods for reducing thesigns and symptoms of axSpA described herein, the subject and/orsubjects in the treated population i) may be biologic disease-modifyinganti-rheumatic drug (bDMARD) naïve or ii) may have had an inadequateresponse or intolerance to a bDMARD (bDMARD-IR) at baseline. In certainembodiments, the subject (or subjects in the treated population) mayhave had a prior inadequate response to, intolerance to, orcontraindication to NSAIDs at baseline.

VIII. Methods of Treating Ankyolosing Spondylitis (AS)

Further provided are methods of treating ankylosing spondylitis (AS).For example, in one aspect, provided is a method of treating AS,including active AS, comprising administering orally once a day a doseof the JAK1 inhibitor to a subject in need thereof in certain amountsand/or at certain intervals. In one aspect, the JAK1 inhibitor isupadacitinib freebase. In one aspect, the JAK1 inhibitor is administeredin an amount sufficient to deliver 15 mg of upadacitinib freebaseequivalent. In one aspect, the JAK1 inhibitor is administered orallyonce a day for at least 14 weeks. In one aspect, the subject is bDMARDnaïve. In one aspect, the subject is bDMARD-IR.

Disease activity/severity for AS may be measured using a variety ofindexes, including those set forth above for the treatment of axSpA. Inone particular aspect, provided is a method of treating AS, includingactive AS, comprising administering a dose of the JAK1 inhibitor to asubject in need thereof in certain amounts and/or at certain intervalsas described herein, wherein the subject achieves an Assessment ofSpondyloArthritis International Society 40 (ASAS40) response followingadministration of the JAK1 inhibitor. In one aspect, the JAK1 inhibitoris upadacitinib freebase. In one aspect, the JAK1 inhibitor isadministered in an amount sufficient to deliver 15 mg of upadacitinibfreebase equivalent. In one aspect, the JAK1 inhibitor is administeredorally once a day for at least 14 weeks. In one aspect, the subject isbDMARD naïve. In one aspect, the subject is bDMARD-IR. In one aspect,the subject is an adult.

In one aspect, the subject achieves an ASAS40 response within 14 weeksof administration of the first dose of the JAK1 inhibitor (including atweek 14). In one aspect, the subject achieves an ASAS40 response within14 weeks of administration of the first dose of the JAK1 inhibitor(including at week 14), and the response is maintained or improved afterweek 14 by continuing to administer a daily dose of the JAK1 inhibitor.In one aspect, the subject achieves an ASAS40 response within 2 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 2). In one aspect, the subject achieves an ASAS40 response within 2weeks of administration of the first dose of the JAK1 inhibitor(including at week 2), and the response is maintained or improved afterweek 2 by continuing to administer a daily dose of the JAK1 inhibitor.In one aspect, the subject achieves an ASAS40 response within 2 weeks,within 4 weeks, within 8 weeks, within 12 weeks, within 14 weeks, within16 weeks, within 18 weeks, within 20 weeks, within 24 weeks, within 32weeks, within 40 weeks, within 52 weeks, within 64 weeks, within 76weeks, within 88 weeks, within 96 weeks, and/or within 104 weeks(including at week 2, week 4, week 8, week 12, week 14, week 16, week18, week 20, week 24, week 32, week 40, week 52, week 64, week 76, week88, week 96, and/or week 104) of administration of the first dose of theJAK1 inhibitor. In one aspect, the subject achieves an ASAS 40 responsewithin 14 weeks of administration of the first dose of the JAK1inhibitor (including at week 14), and the ASAS40 response is maintainedor improved until at least 64 weeks after administration of the firstdose (e.g., up to and including week 64). In one embodiment, the subjectachieves an ASAS 40 response within 2 weeks of administration of thefirst dose (including at week 2), and maintains or improves the ASAS40response until at least 14 weeks after administration of the first dose(e.g., until at least week 14). In one embodiment, the subject achievesan ASAS 40 response within 2 weeks of administration of the first doseof the JAK1 inhibitor (including at week 2), and the ASAS40 response ismaintained or improved until at least 64 weeks after administration ofthe first dose (e.g., up to and including week 64). In one aspect, thesubject altemately or additionally achieves within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14) at least one additional result selected from the groupconsisting of: ASAS partial remission (PR); BASDA150 response; change(improvement) from baseline in MRI SPARCC score for spine (MRI-SpineSPARCC); change (improvement) from baseline in ASDAS; change(improvement) from baseline in BASFI; ASDAS low disease activity (LDA):ASDAS inactive disease (ID); ASDAS major improvement (MI); and ASDASclinically important improvement (CII). In one aspect, the subjectachieves the result within 14 weeks of administration of the first doseof the JAK1 inhibitor (including at week 14), and the result ismaintained or improved after week 14 by continuing to administer a dailydose of the JAK1 inhibitor. In one aspect, the JAK1 inhibitor isupadacitinib freebase. In one aspect, the JAK1 inhibitor is administeredin an amount sufficient to deliver 15 mg of upadacitinib freebaseequivalent. In one aspect, the JAK1 inhibitor is administered orallyonce a day for at least 2 weeks, for at least 4 weeks, for at least 8weeks, for at least 12 weeks, for at least 14 weeks, for at least 16weeks, for at least 18 weeks, for at least 20 weeks, for at least 24weeks, for at least 32 weeks, for at least 40 weeks, for at least 52weeks, for at least 64 weeks, for at least 76 weeks, for at least 88weeks, for at least 96 weeks, and/or for at least 104 weeks. In oneembodiment, the JAK1 inhibitor is administered orally once a day for atleast 14 weeks.

Further provided are methods of treating AS, including active AS, in asubject in need thereof, comprising administering orally once a day adose of a JAK1 inhibitor to a subject in need thereof in certain amountsand/or at certain intervals as described herein, wherein the subjectachieves ASAS partial remission (PR), ASDAS low disease activity (LDA),ASDAS inactive disease (ID), ASDAS major improvement (MI), and/or ASDASclinically important improvement (CII) following administration of theJAK1 inhibitor. In one embodiment, the subject achieves ASAS PR. ASDASLDA, ASDAS ID, ASDAS MI, and/or ASDAS CII within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14). In one embodiment, the subject achieves each result (e.g.,ASAS PR, ASDAS LDA, ASDAS ID. ASDAS MI, and ASDAS CII) within 14 weeksof administration of the first dose of the JAK1 inhibitor (including atweek 14). In one aspect, the subject achieves ASAS PR, ASDAS LDA, ASDASID, ASDAS MI, and/or ASDAS CII within 2 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 2). In one aspect,the subject achieves ASAS PR, ASDAS LDA, ASDAS ID, ASDAS MI, and/orASDAS CII within 2 weeks, within 4 weeks, within 8 weeks, within 12weeks, within 14 weeks, within 16 weeks, within 18 weeks, within 20weeks, within 24 weeks, within 32 weeks, within 40 weeks, within 52weeks, within 64 weeks, within 76 weeks, within 88 weeks, within 96weeks, and/or within 104 weeks (including at week 2, week 4, week 8,week 12, week 14, week 16, week 18, week 20, week 24, week 32, week 40,week 52, week 64, week 76, week 88, week 96, and/or week 104) ofadministration of the first dose of the JAK1 inhibitor. In one aspect,the subject achieves ASAS PR, ASDAS LDA, ASDAS ID, ASDAS MI, and/orASDAS CII within 14 weeks of administration of the first dose of theJAK1 inhibitor (including at week 14), and the response is maintained orimproved after week 14 by continuing to administer a daily dose of theJAK1 inhibitor. In one aspect, the subject achieves ASAS PR, ASDAS LDA,ASDAS ID, ASDAS MI, and/or ASDAS CII within 2 weeks of administration ofthe first dose of the JAK1 inhibitor (including at week 2), and theresponse is maintained or improved after week 2 by continuing toadminister the daily dose of the JAK1 inhibitor. In one aspect, the JAK1inhibitor is upadacitinib freebase. In one aspect, the JAK1 inhibitor isadministered in an amount sufficient to deliver 15 mg of upadacitinibfreebase equivalent. In one aspect, the JAK1 inhibitor is administeredorally once a day for at least 2 weeks, for at least 4 weeks, for atleast 8 weeks, for at least 12 weeks, for at least 14 weeks, for atleast 16 weeks, for at least 18 weeks, for at least 20 weeks, for atleast 24 weeks, for at least 32 weeks, for at least 40 weeks, for atleast 52 weeks, for at least 64 weeks, for at least 76 weeks, for atleast 88 weeks, for at least 96 weeks, and/or for at least 104 weeks. Inone embodiment, the JAK1 inhibitor is administered orally once a day forat least 14 weeks In one aspect, the subject is bDMARD naïve. In oneaspect, the subject is bDMARD-IR. In one aspect, the subject is anadult.

In one aspect, provided is a method of treating AS, including active AS,in a population of subjects in need thereof, the method comprisingadministering a dose of the JAK1 inhibitor to the subjects in certainamounts and/or at certain intervals as described herein, wherein aportion of subjects in the treated population (e.g., a statisticallysignificant population of subjects in the treated population, and/or atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, or at least 45% of the subjects in the treatedpopulation) achieve an ASAS40 response following administration of theJAK1 inhibitor. In one aspect, subjects in the treated populationachieve an ASAS40 response within 14 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 14). In one aspect,subjects in the treated population achieve an ASAS40 response within 14weeks of administration of the first dose of the JAK1 inhibitor(including at week 14), and the response is maintained or improved afterweek 14 by continuing to administer a daily dose of the JAK1 inhibitor.In one aspect, subjects in the treated population achieve an ASAS40response within 2 weeks of administration of the first dose of the JAK1inhibitor (including at week 2). In one aspect, subjects in the treatedpopulation of the subjects achieve an ASAS40 response within 2 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 2), and the response is maintained or improved after week 2 bycontinuing to administer a daily dose of the JAK1 inhibitor. In oneaspect, subjects in the treated population achieve an ASAS40 responsewithin 2 weeks, within 4 weeks, within 8 weeks, within 12 weeks, within14 weeks, within 16 weeks, within 18 weeks, within 20 weeks, within 24weeks, within 32 weeks, within 40 weeks, within 52 weeks, within 64weeks, within 76 weeks, within 88 weeks, within 96 weeks, and/or within104 weeks (including at week 2, week 4, week 8, week 12, week 14, week16, week 18, week 20, week 24, week 32, week 40, week 52, week 64, week76, week 88, week 96, and/or week 104) of administration of the firstdose of the JAK1 inhibitor. In one embodiment, subjects in the treatedpopulation achieve an ASAS40 response within 14 weeks of administrationof the first dose of the JAK1 inhibitor (including at week 14), and theASAS40 response is maintained or improved until at least 64 weeks afteradministration of the first dose (e.g., up to and including week 64). Inone embodiment, subjects in the treated population achieve an ASAS 40response within 2 weeks of administration of the first dose (includingat week 2), and maintains or improves the ASAS40 response until at least14 weeks after administration of the first dose (e.g., until at leastweek 14). In one aspect, subjects in the treated population alternatelyor additionally achieve within 14 weeks of administration of the firstdose of the JAK1 inhibitor (including at week 14) at least oneadditional result selected from the group consisting of ASAS partialremission (PR); BASDAI50 response; change (improvement) from baseline inMRI SPARCC score for spine (MRI-Spine SPARCC); change (improvement) frombaseline in ASDAS; change (improvement) from baseline in BASFI; ASDASlow disease activity (LDA); ASDAS inactive disease (ID); ASDAS majorimprovement (MI); and ASDAS clinically important improvement (CII). Inone aspect, subjects in the treated population achieve the result within14 weeks of administration of the first dose of the JAK1 inhibitor(including at week 14), and the result is maintained or improved afterweek 14 by continuing to administer a daily dose of the JAK1 inhibitor.In certain embodiments, for any of the aforementioned results achieved,a statistically significant population of the subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population, achieve the result. In one aspect,the JAK1 inhibitor is upadacitinib freebase. In one aspect, a dose ofthe JAK1 inhibitor is administered to the population in an amountsufficient to deliver 15 mg of upadacitinib freebase equivalent. In oneaspect, the JAK1 inhibitor is administered to the population orally oncea day for at least 14 weeks. In one aspect, the subjects in thepopulation are bDMARD naïve. In one aspect, the subjects in thepopulation are bDMARD-IR.

Further provided are methods of treating AS, including active AS, in apopulation of subjects in need thereof, the method comprisingadministering orally once a day a dose of the JAK1 inhibitor to asubject in need thereof in certain amounts and/or at certain intervalsas described herein, wherein a portion of the subjects in the treatedpopulation (e.g., a statistically significant population of subjects inthe treated population, and/or at least 10%, at least 15%, at least 20%,at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%of the subjects in the treated population) achieve ASAS partialremission (PR), ASDAS low disease activity (LDA), ASDAS inactive disease(ID), ASDAS major improvement (MI), and/or ASDAS clinically importantimprovement (CII) following administration of the JAK1 inhibitor. In oneaspect, subjects in the treated population achieve ASAS PR, ASDAS LDA,ASDAS ID, ASDAS MI, and/or ASDAS CII within 14 weeks of administrationof the first dose of the JAK1 inhibitor (including at week 14). In oneaspect, subjects in the treated population achieve each result (e.g.,ASAS PR, ASDAS LDA, ASDAS ID, ASDAS MI, and ASDAS CII) within 14 weeksof administration of the first dose of the JAK1 inhibitor (including atweek 14). In one aspect, subjects in the treated population achieve ASASPR, ASDAS LDA, ASDAS ID, ASDAS MI, and/or ASDAS CII within 2 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 2). In one aspect, subjects in the treated population achieve ASASPR, ASDAS LDA, ASDAS ID, ASDAS MI, and/or ASDAS CII within 2 weeks,within 4 weeks, within 8 weeks, within 12 weeks, within 14 weeks, within16 weeks, within 18 weeks, within 20 weeks, within 24 weeks, within 32weeks, within 40 weeks, within 52 weeks, within 64 weeks, within 76weeks, within 88 weeks, within 96 weeks, and/or within 104 weeks(including at week 2, week 4, week 8, week 12, week 14, week 16, week18, week 20, week 24, week 32, week 40, week 52, week 64, week 76, week88, week 96, and/or week 104) of administration of the first dose of theJAK1 inhibitor. In one aspect, subjects in the treated populationachieve ASAS PR, ASDAS LDA, ASDAS ID, ASDAS MI, and/or ASDAS CII within14 weeks of administration of the first dose of the JAK1 inhibitor(including at week 14), and the response is maintained or improved afterweek 14 by continuing to administer the daily dose of the JAK1inhibitor. In one aspect, subjects in the treated population achieveASAS PR, ASDAS LDA, ASDAS ID, ASDAS MI, and/or ASDAS CII within 2 weeksof administration of the first dose of the JAK1 inhibitor (including atweek 2), and the response is maintained or improved after week 2 bycontinuing to administer the daily dose of the JAK1 inhibitor. Incertain embodiments, for any of the aforementioned results achieved, astatistically significant population of subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population, achieve the result. In one aspect,the JAK1 inhibitor is upadacitinib freebase. In one aspect, the JAK1inhibitor is administered in an amount sufficient to deliver 15 mg ofupadacitinib freebase equivalent. In one aspect, the JAK1 inhibitor isadministered orally once a day for at least 2 weeks, for at least 4weeks, for at least 8 weeks, for at least 12 weeks, for at least 14weeks, for at least 16 weeks, for at least 18 weeks, for at least 20weeks, for at least 24 weeks, for at least 32 weeks, for at least 40weeks, for at least 52 weeks, for at least 64 weeks, for at least 76weeks, for at least 88 weeks, for at least 96 weeks, and/or for at least104 weeks. In one embodiment, the JAK1 inhibitor is administered orallyonce a day for at least 14 weeks. In one aspect, the subjects in thepopulation are bDMARD naïve. In one aspect, the subjects in thepopulation are bDMARD-IR. In one aspect, the subjects are adults.

Further provided are methods of reducing the signs and symptoms of AS.In one aspect, provided is a method of reducing the signs and symptomsof AS, including active AS, the method comprising administering a doseof the JAK1 inhibitor to a subject in need thereof in certain amountsand/or at certain intervals. In one aspect, the JAK1 inhibitor isupadacitinib freebase. In one aspect, the JAK1 inhibitor is administeredin an amount sufficient to deliver 15 mg of upadacitinib freebaseequivalent. In one aspect, the JAK1 inhibitor is administered orallyonce a day for at least 14 weeks. In one aspect, the subject is bDMARDnaïve. In one aspect, the subject is bDMARD-IR.

In one aspect of a method of reducing the signs and symptoms of AS,including active AS, wherein the subject achieves within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14), at least one result selected from the group consisting of, anASAS40 response; a change (improvement) from baseline in ASDAS; a change(improvement) from baseline in MRI-Spine SPARCC; ASAS partial remission(PR); a BASDA150 response; a change (improvement) from baseline inBASFI; a change (improvement) from baseline in ASQoL; a change(improvement) from baseline in ASAS Health Index (HI); a change(improvement) from baseline in MASES (enthesitis); a change(improvement) from baseline in BASMIlin (mobility); and a change(improvement) from baseline in WPAI-Axial SpA. In certain embodiments,for any of the aforementioned results achieved, a statisticallysignificant population of the subjects in the treated population, and/orat least 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, or at least 45% of the subjects in the treatedpopulation, achieve the result. In certain embodiments, for any of theaforementioned results achieved, the subject (or subjects in the treatedpopulation) achieve the result or results within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14), and the result (or results) is maintained or improved afterweek 14 by continuing to administer a daily dose of the JAK1 inhibitor.

In another aspect, the subject has (or subjects in the treatedpopulation have) active AS at baseline. In one aspect, the subject (orsubjects in the treated population) fulfills the 1984 modified New YorkCriteria for AS at baseline. In another aspect, the subject (or subjectsin the treated population) fulfills the 2009 ASAS classificationcriteria at baseline. In yet another aspect, the subject (or subjects inthe treated population) fulfills the 1984 modified New York Criteria forAS and the 2009 ASAS classification criteria at baseline. In oneembodiment, the subject (or subjects in the treated population) meets atleast one criteria selected from the group consisting of: (i) a BASDAIscore≥4; (ii) an ASDAS of ≥2.1; and (iii) a Patient's Assessment ofTotal Back Pain (Total Back Pain score) of ≥4 (based on a 0-10 numericalrating scale) at baseline. In one embodiment, the subject (or subjectsin the treated population) has both a BASDAI score≥4 and a Patient'sAssessment of Total Back Pain (Total Back Pain score) of ≥4 at baseline.In another embodiment, the subject (or subjects in the treatedpopulation) has both a BASDAI score≥4 and an ASDAS of ≥2.1 at baseline.In certain embodiments, the subject (or subjects in the treatedpopulation) has (i) a BASDAI score≥4; (ii) an ASDAS of ≥2.1; and (iii) aPatient's Assessment of Total Back Pain (Total Back Pain score) of ≥4(based on a 0-10 numerical rating scale) at baseline. In one aspect, thesubject (or subjects in the treated population) does not have totalspinal ankylosis at baseline. In one aspect, the subject (or subjects inthe treated population) is an adult subject. In another aspect, thesubject (or subjects in the treated population) is a juvenile subject.

In one aspect, the subject (or subjects in the treated population) isbDMARD naïve at baseline. Exemplary bDMARDs include, but are not limitedto, a biologic tumor necrosis factor inhibitor (e.g., adalimumab,etanercept) and interleukin IL)-17 inhibitors (e.g., secukinumab,ixekizumab).

In one aspect, the subject (or subjects in the treated population) isbDMARD naïve at baseline, and further has had i) an inadequate responseor intolerance to at least two NSAIDs (e.g., over at least a four-weekperiod at the maximum recommended or tolerated doses); ii) intoleranceto NSAIDs; and/or iii) contraindication for NSAIDs, as determined by aphysician. Examples of NSAIDs include, but are not limited to,traditional NSAIDs (e.g., ibuprofen) and salicylates (e.g., aspirin).

In certain aspects, the subject (or subjects in the treated population)to be treated is bDMARD naïve at baseline, has had an inadequateresponse or intolerance to at least two NSAIDS (as described above), oran intolerance to or contraindication for NSAIDS, and is furtherreceiving at least one additional therapy. Additional therapies include,but are not limited to concomitant administration of non-biologicDMARDs, NSAIDs, corticosteroids, and combinations thereof. Suitableadditional therapies for use in combination with the methods describedherein include:

-   -   1) Concomitant administration of non-biologic DMARDs, including        methotrexate (MTX), leflunomide (LEF), sulfasalazine (SSZ),        and/or hydroxychloroquine (HCQ). In one embodiment, the subject        is on a stable dose of MTX (≤25 mg/week), SSZ (≤3 g/day),        hydroxychloroquine (≤400 mg/day), and/or leflunomide (≤20        mg/day) for at least 28 days prior to baseline. In some        embodiments, a combination of up to two background non-biologic        DMARDs is allowed, except the combination of MTX and        leflunomide. In one embodiment, the subject has not received any        non-biologic DMARDs (other than MTX, LEF, SSZ, and/or HCQ),        thalidomide, or apremilast within 28 days or five half-lives        (whichever is longer) prior to baseline.    -   2) Concomitant administration of oral corticosteroids. In one        embodiment, the subject is on a stable dose of prednisone (≤10        mg/day), or oral corticosteroid equivalents, for at least 14        days prior to baseline.    -   3) Concomitant administration of NSAIDs, tramadol, a combination        of acetaminophen and codeine or hydrocodone, and/or non-opioid        analgesics. In one embodiment, the subject is on stable dose(s)        for at least 14-days prior baseline.

In another aspect, the subject (or subjects in the treated population)is bDMARD-IR at baseline. In one aspect, the subject has had aninadequate response or intolerance to a bDMARD at baseline. Subjects whoare bDMARD-IR include those subjects who have had prior exposure to onebDMARD (either 1 tumor necrosis factor (TNF) inhibitor (e.g.,adalimumab, etanercept) or 1 interleukin (IL)-17 inhibitor (e.g.,secukinumab, ixekizumab)), and have discontinued the bDMARD due toeither intolerance or lack of efficacy (e.g., as determined by aphysician). In one embodiment, the subject (or subjects in the treatedpopulation) has not had prior exposure to a second bDMARD, if the reasonfor discontinuation was not due to lack of efficacy. In one embodiment,the subject (or subjects in the treated population) has not discontinuedboth a TNF inhibitor and an IL-17 inhibitor due to lack of efficacy.

In certain embodiments, the subject (or subjects in the treatedpopulation) has discontinued the bDMARD prior to receiving the firstdose of the JAK1 inhibitor for:

≥4 weeks for etanercept:

≥8 weeks for adalimumab, infliximab, certolizumab, golimumab, abatacept,tocilizumab, and ixekizumab:

≥12 weeks for ustekinumab;

≥16 weeks for secukinumab;

≥1 year for rituximab or ≥6 months if B cells have returned topre-treatment level or normal reference range (central lab) ifpre-treatment levels are not available; or

≥12 weeks or at least 5 times the mean terminal elimination half-life,whichever is longer, for other bDMARDs.

In one aspect, the subject (or subjects in the treated population) isbDMARD-IR a baseline, and further has had i) an inadequate response orintolerance to at least two NSAIDs (e.g., over at least a four weekperiod at the maximum recommended or tolerated doses); ii) intoleranceto NSAIDs; and/or iii) contraindication for NSAIDs. In one aspect, thesubject (or population of subjects) is bDMARD-IR, and has had aninadequate response to at least two NSAIDS or intolerance to and/orcontraindication for NSAIDs. Examples of NSAIDs include, but are notlimited to, traditional NSAIDs (e.g., ibuprofen) and salicylates (e.g.,aspirin).

In certain aspects, the subject (or subjects in the treated population)to be treated is bDMARD-IR at baseline, has had an inadequate responseor intolerance to at least two NSAIDS (as described above), and/or anintolerance to NSAIDs and/or contraindication for NSAIDS, and is furtherreceiving at least one additional therapy. Additional therapies include,but are not limited to concomitant administration of non-biologicDMARDs, NSAIDs, corticosteroids, and combinations thereof. Suitableadditional therapies for use in combination with the methods describedherein include.

-   -   1) Concomitant administration of non-biologic DMARDs, including        methotrexate (MTX), leflunomide, sulfasalazine (SSZ),        hydroxychloroquine, chloroquine, and/or apremilast. In one        embodiment, the subject is on a stable dose of MTX (≤25        mg/week). SSZ (≤3 g/day), hydroxychloroquine (≤400 mg/day),        chloroquine (≤400 mg/day); leflunomide (≤20 mg/day), or        apremilast (≤60 mg/day)), for at least 28 days prior to        baseline. In some embodiments, a combination of up to two        background non-biologic DMARDs is allowed, except the        combination of MTX and leflunomide.    -   2) Concomitant administration of oral corticosteroids. In one        embodiment, the subject is on a stable dose of prednisone (≤10        mg/day), or oral corticosteroid equivalents, for at least 14        days prior to baseline.    -   3) Concomitant administration of NSAIDs, tramadol, a combination        of acetaminophen/paracetamol and codeine or combination of        acetaminophen/paracetamol and hydrocodone, and/or non-opioid        analgesics. In one embodiment, the subject is on stable dose(s)        for at least 14 days prior to baseline.

In one embodiment, the subject (or subjects in the treated population)is bDMARD-IR at baseline, has not been exposed to any JAK inhibitor, andhas not had any of the following treatments/conditions within thespecified time frame prior to baseline:

-   -   1) Intra-articular joint injections, spinal/paraspinal        injection(s), or parenteral administration of corticosteroids        within 28 days prior to baseline (not including inhaled or        topical corticosteroids);    -   2) Any other non-biologic DMARDs (other than those mentioned        above for concomitant treatment), including thalidomide, within        28 days or 5 half-lives (whichever is longer) of the drug prior        to baseline;    -   3) Opioid analgesics (except for combination of        acetaminophen/paracetamol and codeine or combination of        acetaminophen/paracetamol and hydrocodone) within 14 days prior        to the Baseline Visit:    -   4) No live vaccine within 28 days (or longer if required        locally) prior to the first dose of JAK1 inhibitor, or have        expected need of live vaccination during treatment with the JAK1        inhibitor, including at least 30 days (or longer if required        locally) after the last dose of the JAK1 inhibitor;    -   5) No systemic use of known strong cytochrome P450 3A (CYP3A)        inhibitors during administration of the JAK1 inhibitor, or        strong CYP3A inducers 30 days prior to administration of the        JAK1 inhibitor through the end of treatment;    -   6) Herbal therapies or other traditional medicines with unknown        effects on CYP3A during treatment;    -   7) Investigational drug of chemical or biologic nature within a        minimum of 30 days or 5 half-lives of the drug (whichever is        longer) prior to the first dose of the JAK1 inhibitor; or    -   8) History of an allergic reaction or significant sensitivity to        constituents of the JAK1 inhibitor (and its excipients) and/or        other products in the same class.

In one embodiment, the subject (or subjects in the treated population)is bDMARD naïve or bDMARD-IR, and has not been previously exposed to anyJAK inhibitor at baseline.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD naïve atbaseline, and achieves an ASAS40 response within 14 weeks ofadministration of the first dose (including at week 14). In anotherembodiment, the subject (or subjects in the treated population) isbDMARD naïve at baseline, and achieves an ASAS40 response within 2 weeksof administration of the first dose (including at week 2). In oneembodiment, the subject (or subjects in the treated population) isbDMARD naïve at baseline, and achieves an ASAS40 response within 2 weeksof administration of the first dose (including at week 2) and maintainsthe ASAS40 response until at least 14 weeks after administration of thefirst dose (i.e., including until at least week 14). In one aspect, thesubject (or subjects in the treated population) further achieves ASASPR, ASDAS LDA, ASDAS ID, ASDAS MI, and/or ASDAS CII within 2 weeks ofadministration of the first dose (including at week 2). In certainembodiments, for any of the aforementioned results achieved, astatistically significant population of subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population, achieve the result. In certainembodiments, for any of the aforementioned results achieved, the result(or results) is maintained or improved after achieving the result (orresults) by continuing to administer a daily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD naïve atbaseline, and achieves within 14 weeks of administration of the firstdose (including at week 14) an improvement of ≥40% and absoluteimprovement of ≥2 units (on a scale of 0 to 10) from baseline in each ofthe following 4 (ASAS40) domains:

-   -   a) Patient Global Assessment of disease activity (PtGA) as        assessed on a numeric rating scale (NRS 0-10);    -   b) Patient's Assessment of Total Back Pain (Total Back Pain        score) as assessed on a numeric rating scale (NRS 0-10);    -   c) Bath Ankylosing Spondylitis Functional Index (BASFI); and    -   d) inflammation, as represented by the mean of Questions 5 and 6        of the Bath Ankylosing Spondylitis Disease Activity Index        (BASDAI).

In one embodiment, the above described improvements are achieved within2 weeks of administration of the first dose (including at week 2). Inone embodiment, the improvements are achieved within 14 weeks ofadministration of the first dose (including at week 14). In certainembodiments, a statistically significant population of subjects in thetreated population, and/or at least 10%, at least 15%, at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, or at least 45% ofthe subjects in the treated population, achieve the result. In certainembodiments, for any of the aforementioned results achieved, the result(or results) is maintained or improved after achieving the result (orresults) by continuing to administer a daily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD naïve atbaseline, and alternately or additionally achieves within 14 weeks ofadministration of the first dose (including at week 14) at least oneresult selected from the group consisting of; a) a change (improvement)from baseline in ASDAS (CRP); b) a change (improvement) from baseline inMRI SPARCC score for spine (MRI-Spine SPARCC); c) ASAS partial remission(PR); d) BASDAI50 response; e) a change (improvement) from baseline inBASFI; f) change from baseline in ASQoL; g) a change (improvement) frombaseline in ASAS Health Index (HI); h) a change (improvement) frombaseline in MASES (i.e., for subjects with baseline enthesitis); i) achange (improvement) from baseline in BASMIlin (mobility); and j) achange (improvement) from baseline in WPAI-Axial SpA. In one embodiment,the subject achieves the result within 2 weeks of administration of thefirst dose (including at week 2). In one embodiment, the subjectachieves the result within 14 weeks of administration of the first dose(including at week 14). In certain embodiments, for any of theaforementioned results achieved, a statistically significant populationof subjects in the treated population, and/or at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, or at least 45% of the subjects in the treated population, achieveat least one result. In certain embodiments, for any of theaforementioned results achieved, the result (or results) is maintainedor improved after achieving the result (or results) by continuing toadminister a daily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD naïve atbaseline, and alternately or additionally achieves within 14 weeks ofadministration (including at week 14) of the first dose at least oneresult selected from the group consisting of: a) a change (improvement)from baseline in ASDAS; b) a change (improvement) from baseline in MRISPARCC score for spine (MRI-Spine SPARCC); c) ASAS partial remission(PR); d) BASDAI50 response; and e) a change (improvement) from baselinein BASFI. In one embodiment, each of the results are achieved within 14weeks of administration of the first dose (including at week 14). Incertain embodiments, for any of the aforementioned results achieved, astatistically significant population of subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population, achieve at least one result. Incertain embodiments, for any of the aforementioned results achieved, theresult (or results) is maintained or improved after achieving the result(or results) by continuing to administer a daily dose of the JAK1inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD naïve atbaseline, and alternately or additionally achieves within 14 weeks ofadministration of the first dose (including at week 14) at least oneresult selected from the group consisting of: k) ASAS 20 response;and 1) a change (improvement) from baseline in MRI SPARCC score forsacroiliac (SI) joints (MRI-SI joints SPARCC). In one embodiment, eachof the results are achieved within 14 weeks of administration of thefirst dose (including at week 14). In certain embodiments, for any ofthe aforementioned results achieved, a statistically significantpopulation of subjects in the treated population, and/or at least 10%,at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, or at least 45% of the subjects in the treated population,achieve at least one result. In certain embodiments, for any of theaforementioned results achieved, the result (or results) is maintainedor improved after achieving the result (or results) by continuing toadminister a daily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD naïve atbaseline, and alternately or additionally achieves at least one resultselected from the group consisting of: m) ASAS20 response; n) ASAS40response; o) ASAS PR; p) ASAS 5/6 response; q) ASDAS Inactive Disease(based on ASDAS (CRP) and ASDAS (ESR)); r) ASDAS Low Disease; s) ASDASMajor Improvement (based on ASDAS (CRP) and ASDAS (ESR)); t) ASDASClinically Important Improvement (based on ASDAS (CRP) and ASDAS (ESR);u) change (improvement) from baseline in ASAS HI; v) change(improvement) from baseline in ASDAS(CRP) and ASDAS (ESR); w) change(improvement) from baseline in ASQoL; x) change (improvement) frombaseline in BASDAI; y) change (improvement) from baseline in BASFI; z)change (improvement) from baseline in BASMIlin; aa) change (improvement)from baseline in C-reactive protein (CRP); bb) change (improvement) frombaseline in FACIT-F; cc) change (improvement) from baseline in ISI; dd)change (improvement) from baseline in MASES (in subjects with baselineMASES>0); ee) change (improvement) from baseline in mASSS (withconventional radiograph); ff) change (improvement) from baseline in MRISPARCC score of SI joints; gg) change (improvement) from baseline in MRISPARCC score of spine; hh) change (improvement) from baseline inPatient's Assessment of Total Back Pain score (Total Back Pain score);ii) change (improvement) from baseline in Patient's Assessment ofNocturnal Back Pain (Nocturnal Back Pain); jj) change (improvement) frombaseline in Patient's Global Assessment of Pain (Pt Pain); kk) change(improvement) from baseline in Physician's Global Assessment of DiseaseActivity (PGA-Disease Activity); ll) change (improvement) from baselinein inflammation, as represented by the change (improvement) frombaseline in the mean of Questions 5 and 6 of the BASDAI; mm) change(improvement) from baseline in the Patient's Assessment of Total BackPain, as represented by a change (improvement) from baseline in question2 of BASDAI; nn) change (improvement) from baseline in peripheralpain/swelling, as represented by a change (improvement) in baseline inquestion 3 of BASDAI; oo) change (improvement) from baseline in durationof morning stiffness, as represented by a change (improvement) inbaseline in question 6 of BASDAI; pp) change (improvement) from baselinein Patient's Global Assessment of Disease Activity (PtGA); qq) change(improvement) from baseline in TJC68 and SJC66; rr) change (improvement)from baseline in WPAI-Axial SpA; ss) resolution (improvement) ofdactylitis in subjects with baseline presence of dactylitis; and it)change (improvement) from baseline in total dactylitis count in subjectswith baseline presence of dactylitis. In certain embodiments, for any ofthe aforementioned results achieved, a statistically significantpopulation of subjects in the treated population, and/or at least 10%,at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, or at least 45% of the subjects in the treated population,achieve at least one result. In certain embodiments, for any of theaforementioned results achieved, the result (or results) is maintainedor improved after achieving the result (or results) by continuing toadminister a daily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD naïve atbaseline, and alternately or additionally achieves within 14 weeks ofadministration (including at week 14) of the first dose at least oneresult selected from the group consisting of: q) ASDAS Inactive Disease;r) ASDAS Low Disease, s) ASDAS Major Improvement; and t) ASDASClinically Important Improvement. In one embodiment, each of the resultsare achieved within 14 weeks of administration of the first dose(including at week 14). In certain embodiments, for any of theaforementioned results achieved, a statistically significant populationof subjects in the treated population and/or at least 10%, at least 15%,at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, orat least 45% of the subjects in the treated population, achieved atleast one result. In certain embodiments, for any of the aforementionedresults achieved, the result (or results) is maintained or improvedafter achieving the result (or results) by continuing to administer adaily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD naïve atbaseline, and alternately or additionally achieves at least one resultselected from the group consisting of: ASDAS Inactive Disease, ASDASModerate Disease, ASDAS Low Disease Activity (LDA), ASDAS High Disease,ASDAS Very High Disease, ASDAS Major Improvement, and ASDAS ClinicallyImportant Improvement. In certain embodiments, for any of theaforementioned results achieved, a statistically significant populationof subjects in the treated population, and/or at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, or at least 45% of the subjects in the treated population, achieveat least one result. In certain embodiments, for any of theaforementioned results achieved, the result (or results) is maintainedor improved after achieving the result (or results) by continuing toadminister a daily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD-IR atbaseline, and achieves an ASAS40 response within 14 weeks ofadministration of the first dose (including at week 14). In anotherembodiment, the subject is bDMARD-IR at baseline, and achieves an ASAS40response within 2 weeks of administration of the first dose (includingat week 2). In one embodiment, the subject achieves an ASAS40 responsewithin 2 weeks of administration of the first dose (including at week 2)and maintains the ASAS40 response until at least 14 weeks afteradministration of the first dose (i.e., including until at least week14). In one aspect, the subject (or population of subjects) furtherachieves ASAS PR, ASDAS LDA, ASDAS ID, ASDAS MI, and/or ASDAS CII within2 weeks of administration of the first dose (including at week 2). Incertain embodiments, for any of the aforementioned results achieved, astatistically significant population of subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population, achieved the result. In certainembodiments, for any of the aforementioned results achieved, the result(or results) is maintained or improved after achieving the result (orresults) by continuing to administer a daily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD-IR atbaseline, and alternately or additionally achieves within 14 weeks ofadministration (including at week 14) of the first dose at least oneresult selected from the group consisting of: a) change (improvement)from baseline in ASDAS; b) change (improvement) from baseline in MRISPARCC score for spine (MRI-Spine SPARCC); c) ASAS partial remission(PR); d) BASDAI 50 response; e) change (improvement) from baseline inBASFI; f) change (improvement) from baseline in ASQoL; g) change(improvement) from baseline in ASAS Health Index (HI); h) change(improvement) from baseline in MASES (enthesitis); and i) change(improvement) from baseline in BASMIlin (mobility). In one embodiment,the result is achieved within 14 weeks of administration of the firstdose (including at week 14). In certain embodiments, for any of theaforementioned results achieved, a statistically significant populationof subjects in the treated population, and/or at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, or at least 45% of the subjects in the treated population, achieveat least one result. In certain embodiments, for any of theaforementioned results achieved, the result (or results) is maintainedor improved after achieving the result (or results) by continuing toadminister a daily dose of the JAK1 inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD-IR atbaseline, and alternately or additionally achieves at least one resultselected from the group consisting of: j) ASAS 20 response; and k)change (improvement) from baseline in MRI SPARCC score for SI joints(MRI-SI joints SPARCC). In one embodiment, the result is achieved within14 weeks of administration of the first dose (including at week 14). Incertain embodiments, for any of the aforementioned results achieved, astatistically significant population of subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population, achieve at least one result. Incertain embodiments, for any of the aforementioned results achieved, theresult (or results) is maintained or improved after achieving the result(or results) by continuing to administer a daily dose of the JAK1inhibitor.

In one aspect of the methods of treating AS described herein, thesubject (or subjects in the treated population) is bDMARD-IR atbaseline, and alternately or additionally achieves at least one resultselected from the group consisting of: l) ASAS20 response; m) ASAS40response; n) ASAS PR; o) ASDAS Inactive Disease; p) ASDAS Low Disease;q) ASDAS Major Improvement; r) ASDAS Clinically Important Improvement;s) discontinuation of opioids among subjects with opioid use atbaseline; t) change (improvement) from baseline in ASAS HI; u) change(improvement) from baseline in ASDAS; v) change (improvement) frombaseline in ASQoL; w) change (improvement) from baseline in BASDAI andBASDAI Questions, including change (improvement) from baseline in meanof question 5 and 6 of the BASDAI; x) change (improvement) from baselinein BASFI; y) change (improvement) from baseline in BASMIlin; z) change(improvement) from baseline in high sensitivity C-reactive protein(hsCRP); aa) change (improvement) from baseline in FACIT-F; bb) change(improvement) from baseline in EuroQoL-5D-5L (EQ-5D-5L); cc) change(improvement) from baseline in MASES; dd) change (improvement) frombaseline in mSASSS (with conventional radiograph); ee) change(improvement) from baseline in MRI SPARCC score of SI joints; fT) change(improvement) from baseline in MRI SPARCC score of spine; gg) change(improvement) from baseline in Patient's Assessment of Total Back Painscore (Total Back Pain score); hh) change (improvement) from baseline inPatient's Assessment of Nocturnal Back Pain (Nocturnal Back Pain); ii)change (improvement) from baseline in Patient's Global Assessment ofPain (Pt Pain); jj) change (improvement) from baseline in Physician'sGlobal Assessment of Disease Activity (PGA-Disease Activity); kk) change(improvement) from baseline in Patient's Global Assessment of DiseaseActivity (PtGA); ll) change (improvement) from baseline in SF-36; mm)change (improvement) from baseline in TJC68 and SJC66; nn) change(improvement) from baseline in WPAI-Axial SpA; oo) change (improvement)from baseline in Change of NSAID score; and pp) change (improvement)from baseline in Physical Activity Assessment. In one embodiment, theresult is achieved within 14 weeks of administration of the first dose(including at week 14). In certain embodiments, for any of theaforementioned results achieved, a statistically significant populationof subjects in the treated population, and/or at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, or at least 45% of the subjects in the treated population, achieveat least one result. In certain embodiments, for any of theaforementioned results achieved, the result (or results) is maintainedor improved after achieving the result (or results) by continuing toadminister a daily dose of the JAK1 inhibitor.

IX. Methods of Treating Non-Radiographic Axial Spondyloarthritis(nr-axSnA)

Further provided are methods of treating non-radiographic axialspondyloarthritis (nr-axSpA). In one aspect, provided are methods oftreating active nr-axSpA, comprising administering a dose of the JAK1inhibitor to a subject in need thereof in certain amounts and/or atcertain intervals. In one aspect, the JAK1 inhibitor is upadacitinibfreebase. In one aspect, the JAK1 inhibitor is administered in an amountsufficient to deliver 15 mg of upadacitinib freebase equivalent. In oneaspect, the JAK1 inhibitor is administered orally once a day for atleast 14 weeks. In one aspect, the JAK1 inhibitor is administered orallyonce a day for at least 52 weeks. In one aspect, the subject is bDMARDnaïve. In one aspect, the subject is bDMARD-IR.

Disease activity/severity for nr-axSpA may be measured using a varietyof indexes, including those set forth above for the treatment of axSpA.In one particular aspect, provided is a method of treating nr-axSpA,including active nr-axSpA, comprising administering a dose of the JAK1inhibitor to a subject in need thereof in certain amounts and/or atcertain intervals as described herein, wherein the subject achieves anAssessment of SpondyloArthritis International Society 40 (ASAS40)response following administration of the JAK1 inhibitor. In one aspect,the JAK1 inhibitor is upadacitinib freebase. In one aspect, the JAK1inhibitor is administered in an amount sufficient to deliver 15 mg ofupadacitinib freebase equivalent. In one aspect, the JAK1 inhibitor isadministered orally once a day for at least 14 weeks. In one aspect, theJAK1 inhibitor is administered orally once a day for at least 52 weeks.In one aspect, the subject is bDMARD naïve. In one aspect, the subjectis bDMARD-IR.

In one aspect, the subject achieves an ASAS40 response within 14 weeksof administration of the first dose of the JAK1 inhibitor (including atweek 14). In one aspect, the subject achieves an ASAS40 response within14 weeks of administration of the first dose of the JAK1 inhibitor(including at week 14), and the response is maintained or improved afterweek 14 by continuing to administer a daily dose of the JAK1 inhibitor.In one aspect, the subject achieves an ASAS40 response within 52 weeksof administration of the first dose of the JAK1 inhibitor (including atweek 52). In one aspect, the subject achieves an ASAS40 response within52 weeks of administration of the first dose of the JAK1 inhibitor(including at week 52), and the response is maintained or improved afterweek 52 by continuing to administer a daily dose of the JAK1 inhibitor.In one aspect, the subject achieves an ASAS40 response within 2 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 2). In one aspect, the subject achieves an ASAS40 response within 2weeks of administration of the first dose of the JAK1 inhibitor(including at week 2), and the response is maintained or improved afterweek 2 by continuing to administer a daily dose of the JAK1 inhibitor.In one aspect, the subject achieves an ASAS40 response within 2 weeks,within 4 weeks, within 8 weeks, within 12 weeks, within 14 weeks, within18 weeks, within 24 weeks, within 32 weeks, within 40 weeks, and/orwithin 52 weeks of administration of the first dose of the JAK1inhibitor (including at week 2, week 4, week 8, week 12, week 14, week18, week 24, week 32, week 40, and/or week 52). In one embodiment, thesubject achieves an ASAS 40 response within 2 weeks of administration ofthe first dose (including at week 2), and maintains the ASAS40 responseuntil at least 14 weeks after administration of the first dose (e.g.,until at least week 14). In one embodiment, the subject achieves an ASAS40 response within 2 weeks of administration of the first dose(including at week 2), and maintains the ASAS40 response until at least52 weeks after administration of the first dose (e.g., until at leastweek 52). In one aspect, the JAK1 inhibitor is upadacitinib freebase. Inone aspect, the JAK1 inhibitor is administered in an amount sufficientto deliver 15 mg of upadacitinib freebase equivalent. In one aspect, theJAK1 inhibitor is administered orally once a day for at least 2 weeks,for at least 4 weeks, for at least 8 weeks, for at least 12 weeks, forat least 14 weeks, for at least 18 weeks, for at least 24 weeks, for atleast 32 weeks, for at least 40 weeks, and/or for at least 52 weeks. Inone embodiment, the JAK1 inhibitor is administered orally once a day forat least 14 weeks. In one aspect, the JAK1 inhibitor is administeredorally once a day for at least 52 weeks.

In one aspect, provided is a method of treating nr-axSpA, includingactive nr-axSpA, in a population of subjects in need thereof, the methodcomprising administering a dose of the JAK1 inhibitor to the subjects incertain amounts and/or at certain intervals as described herein, whereina portion of the subjects in the treated population (e.g., astatistically significant population of subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population) achieve an ASAS40 response followingadministration of the JAK1 inhibitor. In one aspect, subjects in thetreated population achieve an ASAS40 response within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14). In one aspect, subjects in the treated population achieve anASAS40 response within 14 weeks of administration of the first dose ofthe JAK1 inhibitor (including at week 14), and the result is maintainedor improved after week 14 by continuing to administer a daily dose ofthe JAK1 inhibitor. In one aspect, subjects in the treated populationachieve an ASAS40 response within 52 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 52). In one aspectsubjects in the treated population achieve an ASAS40 response within 52weeks of administration of the first dose of the JAK1 inhibitor(including at week 52), and the result is maintained or improved afterweek 52 by continuing to administer a daily dose of the JAK1 inhibitor.In one aspect, the JAK1 inhibitor is upadacitinib freebase. In oneaspect, a dose of the JAK1 inhibitor is administered to the subjects inan amount sufficient to deliver 15 mg of upadacitinib freebaseequivalent. In one aspect, the JAK1 inhibitor is administered to thesubjects orally once a day for at least 14 weeks. In one aspect, theJAK1 inhibitor is administered to the subjects orally once a day for atleast 52 weeks. In one aspect, the subjects in the population are bDMARDnaïve. In one aspect, the subjects in the population are bDMARD-IR.

Further provided are methods of reducing the signs and symptoms ofnr-axSpA. In one aspect, provided is a method of reducing the signs andsymptoms of active nr-axSpA, in particular methods comprisingadministering a dose of the JAK1 inhibitor to a subject in need thereofin certain amounts and/or at certain intervals as described herein. Inone aspect, the JAK1 inhibitor is upadacitinib freebase. In one aspect,the JAK1 inhibitor is administered in an amount sufficient to deliver 15mg of upadacitinib freebase equivalent. In one aspect, the JAK1inhibitor is administered orally once a day for at least 14 weeks. Inone aspect, the JAK1 inhibitor is administered orally once a day for atleast 52 weeks. In one aspect, the subject is bDMARD naïve. In oneaspect, the subject is bDMARD-IR.

In one aspect of a method of reducing the signs and symptoms ofnr-axSpA, including active nr-axSpA, the subject (or subjects in thetreated population) achieves within 14 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 14), at least oneresult selected from the group consisting of, an ASAS40 response; achange (improvement) from baseline in ASDAS; a change (improvement) frombaseline in MRI-Spine SPARCC; ASAS partial remission (PR); a BASDAI50response; a change (improvement) from baseline in BASFI; a change(improvement) from baseline in ASQoL; a change (improvement) frombaseline in ASAS Health Index (HI); a change (improvement) from baselinein MASES (enthesitis); and a change (improvement) from baseline inBASMIlin (mobility); or the subject achieves within 52 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 52) an ASAS40 response. In one aspect, the subject (or subjects inthe treated population) achieves the result within 14 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 14), and the result is maintained or improved after week 14 bycontinuing to administer a daily dose of the JAK1 inhibitor. In oneaspect, the subject (or subjects in the treated population) achieves theresult within 52 weeks of administration of the first dose of the JAK1inhibitor (including at week 52), and the result is maintained orimproved after week 52 by continuing to administer a daily dose of theJAK1 inhibitor. In certain embodiments, for any of the aforementionedresults achieved, a statistically significant population of subjects inthe treated population, and/or at least 10%, at least 15%, at least 20%,at least 25%, at least 30%, at least 35%, at least 40%, or at least 45%of the subjects in the treated population, achieve at least one result.

In one aspect, the subject (or population of subjects) in need oftreatment has active nr-axSpA at baseline. In one aspect, the subject(or subjects in the treated population) fulfills the 2009 ASASclassification criteria for axSpA, but does not meet the radiologiccriteria of the 1984 modified New York Criteria for AS at baseline. Inone embodiment, the subject (or subjects in the treated population)meets at least one criteria at baseline selected from the groupconsisting of: (i) a BASDAI score≥4; (ii) an ASDAS of ≥2.1; (iii) aPatient's Assessment of Total Back Pain (Total Back Pain score) of ≥4(based on a 0-10 numerical rating scale); and (iv) an objective sign ofinflammatory activity selected from the group consisting of: a) anobjective sign of active inflammation on MRI of sacroiliac (SI) joints;and b) high-sensitivity C reactive protein (hsCRP)>upper limit of normal(ULN). In one aspect, the subject meets criteria (i), (ii), (iii), and(iv). In one aspect, the subject (or subjects in the treated population)is an adult subject. In another aspect, the subject (or subjects in thetreated population) is a juvenile subject.

In one aspect, the subject (or subjects in the treated population) isbDMARD naïve at baseline. Exemplary bDMARDs include, but are not limitedto, a biologic tumor necrosis factor inhibitor (e.g., adalimumab,etanercept) and interleukin (IL)-17 inhibitors (e.g., secukinumab,ixekizumab).

In another aspect, the subject (or subjects in the treated population)is bDMARD-IR at baseline. In one aspect, the subject (or subjects in thetreated population) has had an inadequate response or intolerance to abDMARD. Subjects who are bDMARD-IR include those subjects who have hadprior exposure to one bDMARD (either 1 tumor necrosis factor (TNF)inhibitor (e.g., adalimumab, etanercept) or 1 interleukin (IL)-17inhibitor (e.g., secukinumab, ixekizumab)), and have discontinued thebDMARD due to either intolerance or lack of efficacy (e.g., asdetermined by a physician). In one embodiment, the subject (or subjectsin the treated population) has not had prior exposure to a secondbDMARD, if the reason for discontinuation was not due to lack ofefficacy. In one embodiment, the subject (or subjects in the treatedpopulation) has not discontinued both a TNF inhibitor and an IL-17inhibitor due to lack of efficacy. In certain embodiments, the subject(or subjects in the treated population) has discontinued the bDMARDprior to receiving the first dose of the JAK1 inhibitor for:

≥4 weeks for etanercept;

≥8 weeks for adalimumab, infliximab, certolizumab, golimumab, abatacept,tocilizumab, and ixekizumab;

≥12 weeks for ustekinumab;

≥16 weeks for secukinumab:

≥1 year for rituximab or ≥6 months if B cells have returned topre-treatment level or normal reference range (central lab) ifpre-treatment levels are not available; or

≥12 weeks or at least 5 times the mean terminal elimination half-life,whichever is longer, for other bDMARDs.

In one aspect, the subject (or subjects in the treated population)further has had i) an inadequate response or intolerance to at least twoNSAIDs (e.g., over at least a four week period at the maximumrecommended or tolerated doses); ii) intolerance to NSAIDs; and/or iii)contraindication for NSAIDs at baseline. Examples of NSAIDs include, butare not limited to, traditional NSAIDs (e.g., ibuprofen) and salicylates(e.g., aspirin).

In certain aspects, the subject (or population of subjects) to betreated is further receiving at least one additional therapy. Additionaltherapies include, but are not limited to concomitant administration ofnon-biologic DMARDs, NSAIDs, corticosteroids, and combinations thereof.Suitable additional therapies for use in combination with the methodsdescribed herein include:

-   -   1) Concomitant administration of non-biologic DMARDs, including        methotrexate (MTX), leflunomide, sulfasalazine (SSZ),        hydroxychloroquine, chloroquine, or apremilast. In one        embodiment, the subject is on a stable dose of MTX (≤25        mg/week), SSZ (≤3 g/day), hydroxychloroquine (≤400 mg/day),        chloroquine (≤400 mg/day); leflunomide (≤20 mg/day), or        apremilast (≤60 mg/day)), for at least 28 days prior to        baseline. In some embodiments, a combination of up to two        background non-biologic DMARDs is allowed, except the        combination of MTX and leflunomide.    -   2) Concomitant administration of oral corticosteroids. In one        embodiment, the subject is on a stable dose of prednisone (≤10        mg/day), or oral corticosteroid equivalents, for at least 14        days prior to baseline.    -   3) Concomitant administration of NSAIDs, tramadol, a combination        of acetaminophen/paracetamol and codeine or combination of        acetaminophen/paracetamol and hydrocodone, and/or non-opioid        analgesics. In one embodiment, the subject is on stable dose(s)        for at least 14 days prior to baseline.

In one embodiment, the subject (or subjects in the treated population)has not been previously exposed to any JAK inhibitor at baseline.

In one aspect of the methods of treating nr-axSpA described herein, thesubject (or subjects in the treated population) alternately oradditionally achieves within 14 weeks of administration of the firstdose (including at week 14) at least one result selected from the groupconsisting of: a) a change (improvement) from baseline in ASDAS; b) achange (improvement) from baseline in MRI SPARCC score for SI joints(MRI-SI joints SPARCC); c) ASAS partial remission (PR); d) BASDAI50response; e) a change (improvement) from baseline in BASFI f) change(improvement) from baseline in ASQoL; g) a change (improvement) frombaseline in ASAS Health Index (HI); h) a change (improvement) frombaseline in MASES (enthesitis); and i) a change (improvement) frombaseline in BASMIlin (mobility); In one embodiment, the subject achievesthe result within 2 weeks of administration of the first dose (includingat week 2). In one embodiment, the subject achieves each of the resultswithin 14 weeks of administration of the first dose (including at week14). In certain embodiments, for any of the aforementioned resultsachieved, the result (or results) is maintained or improved after week 2or week 14 by continuing to administer a daily dose of the JAK1inhibitor. In certain embodiments, for any of the aforementioned resultsachieved, a statistically significant population of subjects in thetreated population, and/or at least 10%, at least 15%, at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, or at least 45% ofthe subjects in the treated population, achieve at least one result.

In one aspect of the methods of treating nr-axSpA described herein, thesubject (or subjects in the treated population) alternately oradditionally achieves within 14 weeks of administration of the firstdose (including at week 14) at least one result selected from the groupconsisting of: j) ASAS 20 response; and k) a change (improvement) frombaseline in MRI SPARCC score for spine (MRI-Spine SPARCC). In oneembodiment, each of the results is achieved within 14 weeks ofadministration of the first dose (including at week 14). In certainembodiments, for any of the aforementioned results achieved, the result(or results) is maintained or improved after week 14 by continuing toadminister a daily dose of the JAK1 inhibitor. In certain embodiments,for any of the aforementioned results achieved, a statisticallysignificant population of subjects in the treated population, and/or atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, or at least 45% of the subjects in the treatedpopulation, achieve at least one result.

In one aspect of the methods of treating nr-axSpA described herein, thesubject (or subjects in the treated population) alternately oradditionally achieves at least one result selected from the groupconsisting of: l) ASAS20 response; m) ASAS40 response; n) ASAS PR; o)ASDAS Inactive Disease; p) ASDAS Low Disease; q) ASDAS MajorImprovement; r) ASDAS Clinically Important Improvement; s)discontinuation of opioids among subjects with opioid use at baseline;t) change (improvement) from baseline in ASAS HI; u) change(improvement) from baseline in ASDAS; v) change (improvement) frombaseline in ASQoL; w) change (improvement) from baseline in BASDAI andBASDAI Questions, including change (improvement) from baseline in meanof questions 5 and 6 of the BASDAI; x) change (improvement) frombaseline in BASFI; y) change (improvement) from baseline in BASMIlin; z)change (improvement) from baseline in high sensitivity C-reactiveprotein (hsCRP); aa) change (improvement) from baseline in FACIT-F; bb)change (improvement) from baseline in EQ-5D-5L; cc) change (improvement)from baseline in MASES; dd) change (improvement) from baseline in mASSS(with conventional radiograph); ee) change (improvement) from baselinein MRI SPARCC score of SI joints; ff) change (improvement) from baselinein MRI SPARCC score of spine; gg) change (improvement) from baseline inPatient's Assessment of Total Back Pain score (Total Back Pain score);hh) change (improvement) from baseline in Patient's Assessment ofNocturnal Back Pain (Nocturnal Back Pain); ii) change (improvement) frombaseline in Patient's Global Assessment of Pain (Pt Pain); jj) change(improvement) from baseline in Physician's Global Assessment of DiseaseActivity (PGA-Disease Activity); kk) change (improvement) from baselinein Patient's Global Assessment of Disease Activity (PtGA); ll) change(improvement) from baseline in SF-36; mm) change (improvement) frombaseline in TJC68 and SJC66; nn) change (improvement) from baseline in(WPAI-Axial SpA); and oo) change (improvement) from baseline in Changeof NSAID score. In certain embodiments, for any of the aforementionedresults achieved, the result (or results) is maintained or improvedafter the result (or results) is achieved by continuing to administer adaily dose of the JAK1 inhibitor. In certain embodiments, for any of theaforementioned results achieved, a statistically significant populationof subjects in the treated population, and/or at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, or at least 45% of the subjects in the treated population, achieveat least one result.

X. Methods of Treating Psoriatic Arthritis (PsA) and Psoriasis (PsO)

Further provided are methods of treating psoriatic arthritis (PsA) andpsoriasis (PsO), including PsO as a skin manifestation of PsA.

In one aspect, provide are methods of treating active PsA comprisingadministering a dose of the JAK1 inhibitor to a subject in need thereofin certain amounts and/or at certain intervals as described herein. Inone aspect, the JAK1 inhibitor is upadacitinib freebase. In one aspect,the JAK1 inhibitor is administered in an amount sufficient to deliver 15mg of upadacitinib freebase equivalent. In one aspect, the JAK1inhibitor is administered in an amount sufficient to deliver 30 mg ofupadacitinib freebase equivalent. In one aspect, the JAK1 inhibitor isadministered orally once a day for at least 12 weeks. In one aspect, thesubject is non-biologic DMARD-IR. In one aspect, the subject isbDMARD-IR. In one aspect, the subject is an adult.

Disease activity/severity for PsA may be measured using a variety ofindexes, including the American College of Rheumatology response rates(e.g., ACR20, ACR50. ACR70); the Health AssessmentQuestionnaire-Disability Index (HAQ-DI); the Static Investigator GlobalAssessment of Psoriasis (sIGA); the Psoriasis Area Severity Index (PASI)(including PASI 75, PASI 90, and PASI 100); the Sharp/van der HeijdeScore (SHS); Minimal Disease Activity (MDA) assessment; Leeds EnthesitisIndex (LEI); Leeds Dactylitis Index (LDI); the 36-Item Short Form HealthSurvey (SF-36); the Patient's Global Assessment of Pain Numerical RatingScale (NRS); the Functional Assessment of Chronic IllnessTherapy-Fatigue (FACIT-F) Questionnaire; the Self-Assessment ofPsoriasis Symptoms (SAPS) Questionnaire; tender joint count (TJC68);swollen joint count (SJC66); the Physician's Global Assessment ofDisease Activity Numeric Rating Scale (PGA-Disease Activity NRS)(numerical rating scale); the Patient's Global Assessment of DiseaseActivity (PtGA); high-sensitivity C Reactive Protein levels (hsCRP);dactylitis count; resolution of dactylitis; resolution of enthesitissites included in the LEI; Spondyloarthritis Research Consortium ofCanada (SPARCC) Enthesitis Index; resolution of enthesitis sitesincluded in the SPARCC Enthesitis Index; total enthesitis count;resolution of enthesitis; Body Surface Area with Psoriasis (BSA-PS);Modified Psoriatic Arthritis Response Criteria (PsARC); Disease ActivityScore 28 (DAS28) (CRP); DAS28 (Erythrocyte Sedimentation Rate (ERS));Psoriatic Arthritis Disease Activity Score (PASDAS); Disease Activity inPsoriatic Arthritis (DAPSA) score; EuroQoL-5D-5L (EQ-5D-5L)Questionnaire; Work Productivity and Activity ImpairmentQuestionnaire-Psoriatic Arthritis (WPAI-PsA); Health ResourceUtilization (HRU) Questionnaire; the Bath Ankylosing Spondylitis DiseaseActivity Index (BASDAI); BASDAI 50 response; Morning Stiffness (mean ofBASDAI Questions 5 and 6); and Ankylosing Spondylitis Disease ActivityScore (ASDAS). These indexes are described in detail in the ClinicalEndpoint Definitions and Examples.

In one particular aspect, provided is a method of treating PsA,including active PsA, comprising administering a dose of the JAK1inhibitor to a subject in need thereof in certain amounts and/or atcertain intervals as described herein, wherein the subject achieves anAmerican College of Rheumatology 20% (ACR20) response followingadministration of the JAK1 inhibitor. In one embodiment, the subjectachieves an ACR 50% (ACR50) response following administration of theJAK1 inhibitor. In one embodiment, the subject achieves an ACR 70%(ACR70) response following administration of the JAK1 inhibitor. In oneaspect, the subject achieves an ACR20, ACR50, or ACR70 response within12 weeks of administration of the first dose of the JAK1 inhibitor(including at week 12). In one aspect, the JAK1 inhibitor isupadacitinib freebase. In one aspect, the JAK1 inhibitor is administeredin an amount sufficient to deliver 15 mg of upadacitinib freebaseequivalent. In one aspect, the JAK1 inhibitor is administered in anamount sufficient to deliver 30 mg of upadacitinib freebase equivalent.In one aspect, the JAK1 inhibitor is administered orally once a day forat least 12 weeks. In one aspect, the subject is non-biologic DMARD-IR.In one aspect, the subject is bDMARD-IR.

In another aspect, provided is a method of treating PsA, includingactive PsA, in a population of subjects in need thereof, the methodcomprising administering a dose of the JAK1 inhibitor to the subjects incertain amounts and/or at certain intervals as described herein, whereina portion of subjects in the treated population (e.g., a statisticallysignificant population of subjects in the treated population, and/or atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, or at least 45% of the subjects in the treatedpopulation) achieve an ACR20. ACR50, or ACR70 response followingadministration of the JAK1 inhibitor. In one aspect, subjects in thetreated population achieve an ACR20, ACR50, or ACR70 response within 12weeks of administration of the first dose of the JAK1 inhibitor(including at week 12). In one aspect, the JAK1 inhibitor isupadacitinib freebase. In one aspect, a dose of the JAK1 inhibitor isadministered to the subjects in an amount sufficient to deliver 15 mg ofupadacitinib freebase equivalent. In one aspect, a dose of the JAK1inhibitor is administered to the subjects in an amount sufficient todeliver 30 mg of upadacitinib freebase equivalent. In one aspect, theJAK1 inhibitor is administered to the subjects orally once a day for atleast 12 weeks.

In certain embodiments, the subject (or subjects in the treatedpopulation) achieve an ACR20 response within 12 weeks of administrationof the first dose of the JAK1 inhibitor (including at week 12). Incertain embodiments, the ACR20 response is maintained or improved afterWeek 12 by continuing to administer a daily dose of the JAK1 inhibitor.In certain embodiments, the subject (or subjects in the treatedpopulation) achieves an ACR20 response within 2 weeks of administrationof the first dose (including at week 2). In certain embodiments, thesubject (or subjects in the treated population) achieves an ACR20response within 2 weeks of administration of the first dose of the JAK1inhibitor (including at week 2), and the ACR20 response is maintained orimproved after Week 2 by continuing to administer a daily dose of theJAK1 inhibitor. In certain embodiments, the subject (or subjects in thetreated population) suffering from active PsA at baseline furtherachieve at least one result selected from the group consisting of: (a)change (improvement) from baseline in Health AssessmentQuestionnaire-Disability Index (HAQ-DI) within 12 weeks ofadministration of the first dose (including at week 12); (b) achieveStatic Investigator Global Assessment (sIGA) of Psoriasis of 0 or 1 andat least a 2-point improvement from baseline at within 16 weeks ofadministration of the first dose (for subjects with baseline sIGA≥2)(including at week 16); (c) achieve Psoriasis Area Severity Index (PASI)75 response within 16 weeks of administration of the first dose (forsubjects with ≥3% BSA psoriasis at baseline) (including at week 16); (d)change (improvement) from baseline in Sharp/van der Heijde Score (SHS)within 24 weeks of administration of the first dose (including at week24); (e) achieve Minimal Disease Activity (MDA) within 24 weeks ofadministration of the first dose (including at week 24); (f) change(improvement) from baseline in Leeds Enthesitis Index (LET) within 24weeks of administration of the first dose, preferably wherein the change(improvement) is a resolution of enthesitis (LEI=0) within 24 weeks ofadministration of the first dose (for subjects with baseline presence ofenthesitis (LEI>0)) (including at week 24); (g) achieve ACR 20 responsewithin 12 weeks of administration of the first dose (non-inferiority ofupadacitinib vs adalimumab) (including at week 12); (h) change(improvement) from baseline in 36-Item Short Form Health Survey (SF-36)within 12 weeks of administration of the first dose (including at week12); and (i) change (improvement) from baseline in Functional Assessmentof Chronic Illness Therapy-Fatigue (FAC1T-F) Questionnaire within 12weeks of administration of the first dose (including at week 12). Incertain embodiments, the subject (or subjects in the treated population)suffering from active PsA at baseline further achieve each result. Incertain embodiments, the subject (or subjects in the treated population)suffering from active PsA at baseline further achieve at least oneresult selected from the group consisting of: (j) ACR 20 response andsuperiority over adalimumab (40 mg every other week) within 12 weeks ofadministration of the first dose (including at week 12); and (k) change(improvement) from baseline in Leeds Dactylitis Index (LDI) within 24weeks of administration of the first dose, preferably wherein the change(improvement) is a resolution of dactylitis (LDI=0) within 24 weeks ofadministration of the first dose (for subjects with baseline presence ofdactylitis (LDI>0)) (including at week 24). In certain embodiments, thesubject (subjects in the treated population) suffering from active PsAat baseline further achieve ACR 20 response and superiority overadalimumab (40 mg every other week) within 12 weeks of administration ofthe first dose (including at week 12). In one aspect, the subject (orsubjects in the treated population) are non-biologic DMARD-IR atbaseline. In one aspect, the subject (or subjects in the treatedpopulation) are bDMARD-IR at baseline. In one aspect, the result ismaintained or improved after week 12, week 16, and/or week 24 bycontinuing to administer a daily dose of the JAK1 inhibitor. In oneaspect, the subject (or subjects in the treated population) furtherachieves a Psoriasis Area Severity Index (PAST) 75 response within 16weeks of administration of the first dose (including at week 16). In oneaspect, the subject (or subjects in the treated population) furtherachieves a PASI 90 response within 16 weeks of administration of thefirst dose (including at week 16). In one aspect, the subject (orsubjects in the treated population) further achieves a PASI 100 responsewithin 16 weeks of administration of the first dose (including at week16). In one aspect the PASI response (e.g., the PASI 75, PASI 90, orPAST 100 response) is maintained or improved after week 16 by continuingto administer a daily dose of the JAK1 inhibitor. In certainembodiments, for any of the aforementioned results achieved, the result(or results) is maintained or improved after the result (or results) isachieved by continuing to administer a daily dose of the JAK1 inhibitor.In certain embodiments, for any of the aforementioned results achieved,a statistically significant population of subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population, achieve at least one result.

Further provided are methods of reducing the signs and symptoms of PsAin a subject in need thereof. In one aspect, provided is a method ofreducing the signs and symptoms of PsA, including active PsA, comprisingadministering a dose of the JAK1 inhibitor to a subject in need thereofin certain amounts and/or at certain intervals as described herein. Inone aspect, the JAK1 inhibitor is upadacitinib freebase. In one aspect,the JAK1 inhibitor is administered in an amount sufficient to deliver 15mg of upadacitinib freebase equivalent. In one aspect, the JAK1inhibitor is administered in an amount sufficient to deliver 30 mg ofupadacitinib freebase equivalent. In one aspect, the JAK1 inhibitor isadministered orally once a day for at least 12 weeks. In one aspect, thesubject is non-biologic DMARD-IR. In one aspect, the subject isbDMARD-IR.

In another aspect, provided is a method of treating PsA, includingactive PsA, in a subject in need thereof, comprising administering adose of the JAK1 inhibitor to the subject in certain amounts and/or atcertain intervals as described herein, wherein the subject achievesMinimal Disease Activity (MDA) following administration of the JAK1inhibitor. In one aspect, the JAK1 inhibitor is upadacitinib freebase,or a pharmaceutically acceptable salt thereof. In one aspect, the JAK1inhibitor is administered in an amount sufficient to deliver 15 mg ofupadacitinib freebase equivalent. In one aspect, the JAK1 inhibitor isadministered in an amount sufficient to deliver 30 mg of upadacitinibfreebase equivalent. In one aspect, the JAK1 inhibitor is administeredorally once a day for at least 24 weeks. In one aspect, the subjectachieves MDA within 24 weeks of administration of the first dose of theJAK1 inhibitor (including at week 24). In one aspect, the subjectachieves MDA within 24 weeks of administration of the first dose of theJAK1 inhibitor (including at week 24), and the MDA is maintained orimproved after week 24 by continuing to administer a daily dose of theJAK1 inhibitor. In one aspect, the subject further achieves a PsoriasisArea Severity Index (PAST) response selected from a PASI 75 response, aPASI 90 response, and a PASI 100 response, within 16 weeks ofadministration of the first dose. In one aspect, the PASI 75, PASI 90,and/or PASI 100 response is maintained or improved after Week 16 bycontinuing to administer the daily dose of the JAK1 inhibitor. In oneaspect, the subject is non-biologic DMARD-IR. In one aspect, the subjectis bDMARD-IR.

In another aspect, provided is a method of treating PsA, includingactive PsA, in a population of subjects in need thereof, the methodcomprising administering a dose of the JAK1 inhibitor to the subjects incertain amounts and/or at certain intervals as described herein, whereina portion of subjects in the treated population (e.g., a statisticallysignificant population of subjects in the treated population, and/or atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, or at least 45% of the subjects in the treatedpopulation) achieve Minimal Disease Activity (MDA) followingadministration of the JAK1 inhibitor. In one aspect, the JAK1 inhibitoris upadacitinib freebase, or a pharmaceutically acceptable salt thereof.In one aspect, a dose of the JAK1 inhibitor is administered to thesubjects in an amount sufficient to deliver 15 mg of upadacitinibfreebase equivalent. In one aspect, a dose of the JAK1 inhibitor isadministered to the subjects in an amount sufficient to deliver 30 mg ofupadacitinib freebase equivalent. In one aspect, the JAK1 inhibitor isadministered to the subjects orally once a day for at least 24 weeks. Inone aspect, subjects in the treated population achieve MDA within 24weeks of administration of the first dose of the JAK1 inhibitor(including at week 24). In one aspect, subjects in the treatedpopulation achieve MDA within 24 weeks of administration of the firstdose of the JAK1 inhibitor (including at week 24), and the MDA ismaintained or improved after week 24 by continuing to administer a dailydose of the JAK1 inhibitor. In one aspect, subjects in the treatedpopulation further achieve a Psoriasis Area Severity Index (PAST)response selected from a PASI 75 response, a PASI 90 response, and aPASI 100 response, within 16 weeks of administration of the first dose.In one aspect, the PASI 75, PASI 90, and/or PASI 100 response ismaintained or improved after Week 16 by continuing to administer thedaily dose of the JAK1 inhibitor. In certain embodiments, for any of theaforementioned results achieved, a statistically significant populationof subjects in the treated population, and/or at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, or at least 45% of the subjects in the treated population, achieveat least one result. In one aspect, the subjects in the treatedpopulation are non-biologic DMARD-IR at baseline. In one aspect, thesubjects in the treated population are bDMARD-IR at baseline.

In one aspect, the subject (or subjects in the treated population)achieves an ACR20, ACR50, or ACR70 response within 12 weeks ofadministration (including at week 12) of the first dose of the JAK1inhibitor. In one aspect, the subject (or subjects in the treatedpopulation) achieves an ACR20, ACR50, or ACR70 response within 12 weeksof administration (including at week 12) of the first dose of the JAK1inhibitor, and the response is maintained or improved after week 12 bycontinuing to administer a daily dose of the JAK1 inhibitor. In oneaspect, the subject (or subjects in the treated population) achieves anACR20, ACR50, or ACR70 response within 2 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 2). In one aspect,the subject (or subjects in the treated population) achieves an ACR20,ACR50, or ACR70 response within 2 weeks of administration of the firstdose of the JAK1 inhibitor (including at week 2), and the response ismaintained or improved after week 12 by continuing to administer a dailydose of the JAK1 inhibitor. In one aspect, the subject (or subjects inthe treated population) achieves an ACR20. ACR50, or ACR70 responsewithin 2 weeks, within 4 weeks, within 8 weeks, within 12 weeks, within16 weeks, within 20 weeks, within 24 weeks, within 28 weeks, within 32weeks, within 36 weeks, within 44 weeks, and/or within 56 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 2, at week 4, at week 8, at week 12, at week 16, at week 20, atweek 24, at week 28, at week 32, at week 36, at week 44, and/or at week56). In one embodiment, the subject (or subjects in the treatedpopulation) achieves an ACR20, ACR50, or ACR70 response within 2 weeksof administration of the first dose (including at week 2), and maintainsthe ACR20, ACR50, or ACR70 response until at least 12 weeks afteradministration of the first dose (e.g., until at least week 12). In oneaspect, the JAK1 inhibitor is upadacitinib freebase. In one aspect, theJAK1 inhibitor is administered in an amount sufficient to deliver 15 mgof upadacitinib freebase equivalent. In one aspect, the JAK1 inhibitoris administered in an amount sufficient to deliver 30 mg of upadacitinibfreebase equivalent. In one aspect, the JAK1 inhibitor is administeredorally once a day for at least 2 weeks, for at least 4 weeks, for atleast 8 weeks, for at least 12 weeks, at least 16 weeks, for at least 20weeks, for at least 24 weeks, for at least 28 weeks, for at least 32weeks, for at least 36 weeks, for at least 44 weeks, and/or for at least56 weeks. In one embodiment, the JAK1 inhibitor is administered orallyonce a day for at least 12 weeks. In certain embodiments, for any of theaforementioned results achieved, a statistically significant populationof subjects in the treated population, and/or at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, or at least 45% of the subjects in the treated population, achieveat least one result.

In one aspect of a method of reducing the signs and symptoms of PsA,including active PsA, the subject (or subjects in the treatedpopulation) achieves at least one result selected from the groupconsisting of: an ACR20 response within 12 weeks of administration ofthe first dose of the JAK1 inhibitor (including at week 12); a change(improvement) from baseline in HAQ-DI within 12 weeks of administrationof the first dose of the JAK1 inhibitor (including at week 12); a sIGAof 0 or 1 and at least a 2 point improvement from baseline within 16weeks of administration of the first dose of the JAK1 inhibitor(including at week 16); PASI 75 response (for subjects with ≥3% BodySurface Area psoriasis at baseline) within 16 weeks of administration ofthe first dose of the JAK1 inhibitor (including at week 16); a change(improvement) from baseline in SHS within 24 weeks of administration ofthe first dose of the JAK1 inhibitor (including at week 24); MinimalDisease Activity within 24 weeks of administration of the first dose ofthe JAK1 inhibitor (including at week 24); a change (improvement) frombaseline in LEI within 24 weeks of administration of the first dose ofthe JAK1 inhibitor (including at week 24); a change (improvement) frombaseline in LDI within 24 weeks of administration of the first dose ofthe JAK1 inhibitor (including at week 24); a change (improvement) frombaseline in SF-36 within 12 weeks of administration of the first dose ofthe JAK1 inhibitor (including at week 12); change (improvement) frombaseline in Patient's Global Assessment of Pain (Pt Pain) (numericalrating scale) within 12 weeks of administration of the first dose of theJAK1 inhibitor (including at week 12); change (improvement) frombaseline in FACIT-F within 12 weeks of administration of the first doseof the JAK1 inhibitor (including at week 12); change (improvement) frombaseline in SAPS Questionnaire within 16 weeks of administration of thefirst dose of the JAK1 inhibitor (including at week 16); ACR50 or ACR70response within 12 weeks of administration of the first dose of the JAK1inhibitor (including at week 12); and ACR20 response within 2 weeks ofadministration of the first dose of the JAK1 inhibitor (including atweek 2). In one aspect, the result is maintained or improved after week2, week 12, week 16, or week 24 by continuing to administer a daily doseof the JAK1 inhibitor. In certain embodiments, for any of theaforementioned results achieved, a statistically significant populationof subjects in the treated population, and/or at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, or at least 45% of the subjects in the treated population, achieveat least one result.

Further provided are methods of inhibiting the progression of structuraldamage of PsA in a subject in need thereof. In one aspect, provided is amethod of inhibiting the progression of structural damage of PsA,including active PsA, comprising administering a dose of the JAK1inhibitor to a subject in need thereof in certain amounts and/or atcertain intervals as described herein. In one aspect, the JAK1 inhibitoris upadacitinib freebase. In one aspect, the JAK1 inhibitor isadministered in an amount sufficient to deliver 15 mg of upadacitinibfreebase equivalent. In one aspect, the JAK1 inhibitor is administeredin an amount sufficient to deliver 30 mg of upadacitinib freebaseequivalent. In one aspect, the JAK1 inhibitor is administered orallyonce a day for at least 12 weeks. In one aspect, the subject isnon-biologic DMARD-IR. In one aspect, the subject is bDMARD-IR.

Further provided are methods of improving physical function in a subjectin need thereof. In one aspect, provided is a method of improvingphysical function of PsA, including active PsA, comprising administeringa dose of the JAK1 inhibitor to a subject in need thereof in certainamounts and/or at certain intervals as described herein. In one aspect,the JAK1 inhibitor is upadacitinib freebase. In one aspect, the JAK1inhibitor is administered in an amount sufficient to deliver 15 mg ofupadacitinib freebase equivalent. In one aspect, the JAK1 inhibitor isadministered in an amount sufficient to deliver 30 mg of upadacitinibfreebase equivalent. In one aspect, the JAK1 inhibitor is administeredorally once a day for at least 12 weeks. In one aspect, the subject isnon-biologic DMARD-IR. In one aspect, the subject is bDMARD-IR.

Further provided are methods of preventing structural progression of PsAin a subject in need thereof. In one aspect, provided is a method ofpreventing structural progression of PsA, including active PsA,comprising administering a dose of the JAK1 inhibitor to a subject inneed thereof in certain amounts and/or at certain intervals as describedherein. In one aspect, the JAK1 inhibitor is upadacitinib freebase. Inone aspect, the JAK1 inhibitor is administered in an amount sufficientto deliver 15 mg of upadacitinib freebase equivalent. In one aspect, theJAK1 inhibitor is administered in an amount sufficient to deliver 30 mgof upadacitinib freebase equivalent. In one aspect, the JAK1 inhibitoris administered orally once a day for at least 12 weeks. In one aspect,the subject is non-biologic DMARD-IR. In one aspect, the subject isbDMARD-IR.

In one aspect, the subject (or population of subjects) in need oftreatment has active PsA at baseline. In one aspect, the subject (orpopulation of subjects) in need of treatment and with active PsA atbaseline further have moderately to severely active psoriatic arthritisat baseline, as determined by a physician. In one aspect, the subject(or subjects in the treated population) has a clinical diagnosis of PsAwith symptoms onset at least six months prior to baseline. In oneaspect, the subject (or subjects in the treated population) fulfills theClassification Criteria for PsA (CASPAR) criteria at baseline. In oneembodiment, the subject (or subjects in the treated population) meets atleast one criteria selected from the group consisting of: (i) ≥3 tenderjoints (based on 68 joint counts); and (ii) ≥3 swollen joints (based on66 joint counts) at baseline. In one aspect the subject (or subjects inthe treated population) has ≥3 tender joints (based on 68 joint counts);and (ii) ≥3 swollen joints (based on 66 joint counts) at baseline. Incertain embodiments, the subject (or subjects in the treated population)may have ≥5 tender joints (based on 68 joint counts) and ≥5 swollenjoints (based on 66 joint counts) at baseline. In one aspect, thesubject (or subjects in the treated population) meets at least onecriteria selected from the group consisting of ≥1 erosion on x-ray asdetermined by central imaging review, and hs-CRP>laboratory definedupper limit of normal (ULN), at baseline. In one aspect, the subject (orsubjects in the treated population) does not have Minimal DiseaseActivity (responders and non-responders) for PsA at baseline. In oneaspect, the subject (or subjects in the treated population) has adiagnosis of active plaque psoriasis or a documented history of plaquepsoriasis (e.g., as determined by a physician) at baseline. In oneaspect, the subject (or subjects in the treated population) is an adultsubject. In another aspect, the subject (or subjects in the treatedpopulation) is a juvenile subject.

In one aspect, the subject (or subjects in the treated population) isnon-biologic DMARD-IR at baseline. In one aspect, the subject (orsubjects in the treated population) has had an inadequate response orintolerance to treatment with a non-biologic DMARD. Subjects who arenon-biologic DMARD-IR include those subjects who have an intolerance toor contraindication for non-biologic DMARDs (e.g., as determined by aphysician), or who have had an inadequate response (i.e., a lack ofefficacy after a minimum 12-week duration of therapy) to previous orconcomitant treatment with at least one non-biologic DMARD at maximallytolerated dose or up to a dose set forth as follows:

-   -   i) methotrexate (MTX): ≤25 mg/week, or ≥15 to ≤25 mg/week, or        ≥10 mg/week in subjects who are intolerant of MTX at doses≥12.5        mg/week after complete titration;    -   ii) sulfasalazine (SSZ): ≤3000 mg/day;    -   iii) leflunomide (LEF): ≤20 mg/day;    -   iv) apremilast: ≤60 mg/day;    -   v) hydroxychloroquine (HCQ): ≤400 mg/day;    -   vi) bucillamine: ≤300 mg/day; or    -   vii) iguratimod: ≤50 mg/day) for ≥12 weeks and at stable dose        for ≥4 weeks prior to the baseline. In one aspect, the subject        has not been exposed to any additional non-biologic DMARDs.

In certain aspects, the subject (or population of subjects) to betreated is non-biologic DMARD-IR and is further receiving at least oneadditional therapy. Suitable additional therapies include:

-   -   1) Stable doses of non-biologic DMARDs. In one aspect, the        subject is receiving a concomitant DMARD treatment at baseline.        In one aspect, the subject is on ≤2 non-biologic DMARDs (except        the combination of MTX and leflunomide). Suitable doses for MTX,        SSZ, LEF, apremilast, HCQ, bucillamine, and iguratimod are set        forth above. In one aspect, the subject is not on any        non-biologic DMARD other than MTX, SSZ, LEF, apremilast. HCQ,        bucillamine, iguratimod, or the combination of MTX and LEF. In        one embodiment, the subject is not receiving concomitant        treatment of any non-biologic DMARD other than MTX, SSZ,        leflunomide, apremilast, HCQ, bucillamine, or iguratimod.    -   2) Stable doses of NSAIDs, acetaminophen/paracetamol,        low-potency opiates (tramadol or combination of acetaminophen        and codeine or hydrocodone), oral corticosteroids (equivalent to        prednisone≤10 mg/day), or inhaled corticosteroids for stable        medical conditions. In one embodiment, the subject has been        receiving stable doses of such additional therapies for ≥1 week        prior to baseline.

In one aspect, the subject (or population of subjects) to be treated isnon-biologic DMARD-IR, and may discontinue treatment with at least onenon-biologic DMARD prior to baseline in order to comply with theconcomitant administration of non-biologic DMARD protocols set forthabove (e.g., concomitant administration of ≤2 non-biologic DMARDs (notincluding the combination of MTX and leflunomide), selected from MTX,SSZ, leflunomide, apremilast, HCQ, bucillamine, and iguratimod) atstable doses. In one embodiment, the subject has discontinued thetreatment with the non-biologic DMARD prior to baseline for:

-   -   ≥8 weeks for LEF if no elimination procedure was followed, or        adheres to an elimination procedure (i.e., 11 days with        cholestyramine, or 30 day washout with activated charcoal or as        per local label); or    -   ≥4 weeks for all other non-biologic DMARDs.

In another aspect, the subject (or subjects in the treated population)is bDMARD-IR at baseline. In one aspect, the subject (or subjects in thetreated population) has had an inadequate response or intolerance to abDMARD. Subjects who are bDMARD-IR include those subjects who have hadprior exposure to at least one bDMARD prior to baseline and have had aninadequate response due to lack of efficacy after a minimum 12-weekduration of therapy, or who are intolerance to treatment with at least 1bDMARD. In one aspect, the subject (or subjects in the treatedpopulation) has discontinued all bDMARDs prior to baseline. In certainembodiments, the subject (or subjects in the treated population) hasdiscontinued the bDMARD prior to receiving the first dose of the JAK1inhibitor for:

-   -   ≥4 weeks for etanercept;    -   ≥8 weeks for adalimumab, infliximab, certolizumab, golimumab,        abatacept, tocilizumab, and ixekizumab;    -   ≥12 weeks for ustekinumab;    -   ≥16 weeks for secukinumab; or    -   ≥1 year for rituximab or ≥6 months if B cells have returned to        pre-treatment level or normal reference range (central lab) if        pre-treatment levels are not available.

In certain aspects, the subject (or population of subjects) to betreated is bDMARD-IR, and is further receiving at least one additionaltherapy. Additional therapies include but are not limited to concomitantadministration of non-biologic DMARDs and/or NSAIDs, corticosteroids,and combinations thereof. Suitable additional therapies for use incombination with the methods of described herein include:

-   -   1) Concomitant administration of ≤2 non-biologic DMARDs (not        including the combination of MTX and leflunomide), selected from        methotrexate (MTX), sulfasalazine (SSZ), leflunomide,        apremilast, hydroxychloroquine (HCQ), bucillamine, and        iguratimod. In one embodiment, the subject is on a stable dose        of MTX (≤25 mg/week). SSZ (≤3000 mg/day), leflunomide (LEF) (≤20        mg/day), apremilast (560 mg/day). HCQ (≤400 mg/day), bucillamine        (≤300 mg/day) or iguratimod (≤50 mg/day) for ≥12 weeks and for        ≥4 weeks prior to the baseline. In one embodiment, the subject        is not receiving concomitant treatment of any non-biologic DMARD        other than MTX, SSZ, leflunomide, apremilast. HCQ, bucillamine,        or iguratimod.    -   2) Concomitant administration of stable doses of NSAIDs,        acetaminophen/paracetamol, low-potency opiates (tramadol or        combination of acetaminophen and codeine or hydrocodone), oral        corticosteroids (equivalent to prednisone≤10 mg/day), or inhaled        corticosteroids at a stable dose for ≥1 weeks prior to the        baseline.

In one aspect, the subject (or population of subjects) to be treated isbDMARD-IR and has received previous treatment with at least onenon-biologic DMARD. In one embodiment, such a subject may discontinuetreatment with at least one non-biologic DMARD prior to baseline inorder to comply with the concomitant administration of non-biologicDMARD protocols set forth above (e.g., concomitant administration of ≤2non-biologic DMARDs (not including the combination of MTX andleflunomide), selected from MTX, SSZ, leflunomide, apremilast, HCQ,bucillamine, and iguratimod) at stable doses. In one embodiment, thesubject has discontinued the treatment with the non-biologic DMARD priorto baseline for:

-   -   ≥8 weeks for LEF if no elimination procedure was followed, or        adheres to an elimination procedure (i.e., 11 days with        cholestyramine, or 30 day washout with activated charcoal or as        per local label); or    -   ≥4 weeks for all other non-biologic DMARDs.

In one aspect, the subject (or subjects in the treated population) isbDMARD-IR or non-biologic DMARD-IR at baseline, and has discontinued allopiates (except for tramadol, or combination of acetaminophen andcodeine or hydrocodone) at least 1 week prior to baseline. In oneaspect, the subject (or subjects in the treated population) is bDMARD-IRor non-biologic DMARD-IR at baseline, and has not been previouslyexposed to any JAK inhibitor. In one aspect, the subject (or subjects inthe treated population) is bDMARD-IR or non-biologic DMARD-IR atbaseline, and is not receiving current treatment (i.e., treatment at thetime of administration of the JAK1 inhibitor) with >2 non-biologicDMARDs, or treatment with a DMARD other than MTX, SSZ, LEF, apremilast,HCQ, bucillamine or iguratimod, or use of MTX in combination with LEF atbaseline. In one embodiment, the subject (or subjects in the treatedpopulation) is non-biologic DMARD-IR or bDMARD-IR, and does not have ahistory of fibromyalgia, any arthritis with onset prior to age 17 years,or a current diagnosis of inflammatory joint disease other than PsA(including, but not limited to, rheumatoid arthritis, gout, overlapconnective tissue diseases, scleroderma, polymyositis, dermatomyositis,and systemic lupus erythermatosus).

In one aspect of the methods of treating PsA described herein, thesubject (or subjects in the treated population) is non-biologic DMARD-IRat baseline, and alternately or additionally achieves at least oneresult selected from the group consisting of: a) change (improvement)from baseline in HAQ-DI within 12 weeks of administration of the firstdose (including at week 12); b) sIGA of 0 or 1 and at least a 2-pointimprovement from baseline within 16 weeks of administration of the firstdose (including at week 16); c) PASI 75 response within 16 weeks ofadministration of the first dose (including at week 16) (for subjectswith ≥3% Body Surface Area (BSA) psoriasis at baseline); d) change(improvement) from baseline in SHS within 24 weeks of administration ofthe first dose (including at week 24); e) Minimal Disease Activity (MDA)within 24 weeks of administration of the first dose (including at week24); f) change (improvement) from baseline in LEI within 24 weeks ofadministration of the first dose (including at week 24); g) change(improvement) from baseline in LDI within 24 weeks of administration ofthe first dose (including at week 24); h) change (improvement) frombaseline in SF-36 within 12 weeks of administration of the first dose(including at week 12); i) change (improvement) from baseline inPatient's Global Assessment of Pain (Pt Pain) Numerical Rating Scale(NRS) within 12 weeks of administration of the first dose (including atweek 12); j) change (improvement) from baseline in FACIT-F Questionnairewithin 12 weeks of administration of the first dose (including at week12); and k) change (improvement) from baseline in SAPS Questionnairewithin 16 weeks of administration of the first dose (including at week16). In one aspect, the result is maintained or improved after week 12,week 16, or week 24 by continuing to administer a daily dose of the JAK1inhibitor. In certain embodiments, for any of the aforementioned resultsachieved, a statistically significant population of subjects in thetreated population, and/or at least 10%, at least 15%, at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, or at least 45% ofthe subjects in the treated population, achieve at least one result.

In one aspect of the methods of treating PsA described herein, thesubject (or subjects in the treated population) is non-biologic DMARD-IRand may alternately or additionally achieve a result that isnon-inferior or superior to the result achieved by administration ofadalimumab. In one aspect, the result is superior or non-inferior to theresult achieved when a subject is administered 40 mg doses of adalimumabevery other week for 12 weeks. Examples of suitable formulations ofadalimumab are described in Example 1. In one aspect, the subjectachieves within 12 weeks of administration of the first dose (includingat week 12) at least one result selected from the group consisting of:i) ACR20 that is non-inferior as compared to adalimumab; ii) ACR20response that is superior as compared to adalimumab; change(improvement) from baseline in Patient's Global Assessment of Pain (PtPain) Numerical Rating Scale (NRS) that is superior as compared toadalimumab; iv) change (improvement) from baseline in HAQ-DI that issuperior as compared to adalimumab. In one aspect, the result (orresults) is maintained or improved after the result (or results) isachieved by continuing to administer a daily dose of the JAK1 inhibitor.In certain embodiments, for any of the aforementioned results achieved,a statistically significant population of subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population, achieve at least one result.

In one aspect of the methods of treating PsA described herein, thesubject (or subjects in the treated population) is non-biologic DMARD-IRat baseline, and alternately or additionally achieves least one resultselected from the group consisting of: 1) ACR50 or ACR70 response ratewithin 12 weeks of administration of the first dose (including at week12); and m) ACR20 response rate within 2 weeks of administration of thefirst dose (including at week 2). In one aspect, the result ismaintained or improved after week 2 or week 12 by continuing toadminister a daily dose of the JAK1 inhibitor. In certain embodiments,for any of the aforementioned results achieved, a statisticallysignificant population of subjects in the treated population, and/or atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, or at least 45% of the subjects in the treatedpopulation, achieve at least one result.

In one aspect of the methods of treating PsA described herein, thesubject (or subjects in the treated population) is non-biologic DMARD-IRat baseline, and alternately or additionally achieves at least oneresult selected from the group consisting of; n) no radiographicprogression, as demonstrated by change (improvement) in baseline in SHSof ≤0; o) change (improvement) from baseline in at least one individualcomponents of ACR response selected from the group consisting of: (i)change (improvement) from baseline in Tender Joint Count (TJC68) (0-68);(ii) change (improvement) from baseline in Swollen Joint Count (SJC66)(0-66); (iii) change (improvement) from baseline in Physician GlobalAssessment-Disease Activity (PGA-Disease Activity) Numerical RatingScale (NRS); (iv) change (improvement) from baseline in Patient's GlobalAssessment (PtGA)-Disease Activity Numerical Rating Scale (NRS); (v)change (improvement) from baseline in Patient's Global Assessment ofPain (Pt Pain) Numerical Rating Scale (NRS); (vi) change (improvement)from baseline in HAQ-DI; and (vii) change (improvement) from baseline inhs-CRP; p) ACR20. ACR5, or ACR70 response; q) change (improvement) frombaseline in LDI; r) change (improvement) from baseline in dactylitiscount; s) resolution of dactylitis; t) change (improvement) frombaseline in LEI; u) resolution of enthesitis sites included in the LEI;v) change (improvement) from baseline in SPARCC Enthesitis Index; w)resolution of enthesitis sites included in the SPARCC Enthesitis Index;x) change (improvement) from baseline in total enthesitis count; y)resolution of enthesitis; z) PASI 75, PSA 90, or PSA 100 response insubjects with ≥3% Body Surface Area (BSA) psoriasis at baseline; aa)sIGA score of 0 or 1 and at least a 2-point improvement from baseline;bb) Body Surface Area with Psoriasis (BSA-PS); cc) change (improvement)from baseline in PsARC; dd) change (improvement) from baseline in DAS28(CRP); ee) change (improvement) from baseline in DAS28 (ESR); ff) change(improvement) from baseline in PASDAS; gg) change (improvement) frombaseline in DAPSA score; hh) change (improvement) from baseline inSF-36; ii) change (improvement) from baseline in FACIT-F Questionnaire;jj) change (improvement) from baseline in EQ-5D-5L Questionnaire; kk)change (improvement) from baseline in WPAI-PsA Questionnaire; ll) change(improvement) from baseline in HRU Questionnaire; mm) change(improvement) from baseline in SAPS Questionnaire; nn) change(improvement) from baseline in BASDAI; oo) BASDAI 50 response rate; pp)change (improvement) from baseline in Morning stiffness, measured asmean of BASDAI Questions 5 and 6; qq) change (improvement) from baselinein ASDAS; rr) ASDAS Inactive Disease, ss) ASDAS Major Improvement; tt)ASDAS Clinically Important Improvement; and uu) clinically meaningfulimprovement in HAQ-DI (≥0.35). In one aspect, the result (or results) ismaintained or improved after achieving the result (or results) bycontinuing to administer a daily dose of the JAK1 inhibitor. In certainembodiments, for any of the aforementioned results achieved, astatistically significant population of subjects in the treatedpopulation, and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population, achieve at least one result.

In one aspect of the methods of treating PsA described herein, thesubject (or subjects in the treated population) is bDMARD-IR atbaseline, and alternately or additionally achieves least one resultselected from the group consisting of: a) change (improvement) frombaseline in HAQ-DI within 12 weeks of administration of the first dose(including at week 12); b) sIGA of Psoriasis of 0 or 1 and at least a2-point improvement from baseline within 16 weeks of administration ofthe first dose (including at week 16); c) PASI 75 response within 16weeks of administration of the first dose (including at week 16) forsubjects with ≥3% Body Surface Area (BSA) psoriasis at baseline; d)Minimal Disease Activity (MDA) within 24 weeks of administration of thefirst dose (including at week 24); e) change (improvement) from baselinein SF-36 within 12 weeks of administration of the first dose (includingat week 12); f) change (improvement) from baseline in FACIT-FQuestionnaire within 12 weeks of administration of the first dose(including at week 12); and g) change (improvement) from baseline inSAPS Questionnaire within 16 weeks of administration of the first dose(including at week 16). In one aspect, the result is maintained orimproved after week 12, week 16, or week 24 by continuing to administera daily dose of the JAK1 inhibitor. In certain embodiments, for any ofthe aforementioned results achieved, a statistically significantpopulation of subjects in the treated population, and/or at least 10%,at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, or at least 45% of the subjects in the treated population,achieve at least one result.

In one aspect of the methods of treating PsA described herein, thesubject (or subjects in the treated population) is bDMARD-IR atbaseline, and alternately or additionally achieves at least one resultselected from the group consisting of; h) ACR50 or ACR70 response within12 weeks of administration of the first dose (including at week 12); andi) ACR20 response within 2 weeks of administration of the first dose(including at week 2). In one aspect, the result is maintained orimproved after week 2 or week 12 by continuing to administer a dailydose of the JAK1 inhibitor. In certain embodiments, for any of theaforementioned results achieved, a statistically significant populationof subjects in the treated population, and/or at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, or at least 45% of the subjects in the treated population, achieveat least one result.

In one aspect of the methods of treating PsA described herein, thesubject (or subjects in the treated population) is bDMARD-IR atbaseline, and alternately or additionally achieves at least one resultselected from the group consisting of: j) change (improvement) frombaseline in at least one individual component of an ACR responseselected from the group consisting of: (i) change (improvement) frombaseline in Tender Joint Count (TJC68) (0-68); (ii) change (improvement)from baseline in Swollen Joint Count (SJC66) (0-66); (iii) change(improvement) from baseline in Physician Global Assessment-DiseaseActivity (PGA-Disease Activity) Numerical Rating Scale (NRS); (iv)change (improvement) from baseline in Patient's Global Assessment(PtGA)-Disease Activity Numerical Rating Scale (NRS); (v) change(improvement) from baseline in Patient's Global Assessment of Pain (PtPain) Numerical Rating Scale (NRS); (vi) change (improvement) frombaseline in Health Assessment Questionnaire-Disability Index (HAQ-DI);and (vii) change (improvement) from baseline in High-Sensitivity CReactive Protein (hs-CRP); k) ACR20, ACR50, or ACR70 response rate; 1)change (improvement) from baseline in LDI; m) change (improvement) frombaseline in dactylitis count; n) resolution of dactylitis; n) change(improvement) from baseline in LEI; o) resolution of enthesitis sitesincluded in the LEI; p) change (improvement) from baseline in SPARCCEnthesitis Index; q) resolution of enthesitis sites included in theSPARCC Enthesitis Index; r) change (improvement) from baseline in totalenthesitis count; s) resolution of enthesitis; t) PASI 75, PASI 90, orPASI 100 response in subjects with ≥3% Body Surface Area (BSA) psoriasisat baseline; u) sIGA score of 0 or 1 and at least a 2-point improvementfrom baseline; v) Body Surface Area with Psoriasis (BSA-PS); w) change(improvement) from baseline in PsARC; x) change (improvement) frombaseline in DAS28 (CRP); y) change (improvement) from baseline in DAS28(ESR); z) change (improvement) from baseline in PASDAS; aa) change(improvement) from baseline in DAPSA score; bb) change (improvement)from baseline in SF-36; cc) change (improvement) from baseline inFACIT-F Questionnaire; dd) change (improvement) from baseline inEQ-5D-5L Questionnaire; ee) change (improvement) from baseline inWPAI-PsA Questionnaire; ff) change (improvement) from baseline in HRUQuestionnaire; gg) change (improvement) from baseline in SAPSQuestionnaire; hh) change (improvement) from baseline in BASDAI; ii)BASDAI 50 response; jj) change (improvement) from baseline in Morningstiffness, measured as mean of BASDAI Questions 5 and 6; kk) change(improvement) from baseline in ASDAS; ll) ASDAS Inactive Disease; mm)ASDAS Major Improvement; nn) ASDAS Clinically Important Improvement; andoo) clinically meaningful improvement in HAQ-DI (≥0.35). In one aspect,the result (or results) is maintained or improved after achieving theresult (or results) by continuing to administer a daily dose of the JAK1inhibitor. In certain embodiments, for any of the aforementioned resultsachieved, a statistically significant population of subjects in thetreated population, and/or at least 10%, at least 15%, at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, or at least 45% ofthe subjects in the treated population, achieve at least one result.

In another aspect, provided is a method of treating active PsA in asubject in need thereof, the method comprising orally administering tothe subject once a day for at least 16 weeks a dose of upadacitinibfreebase, or a pharmaceutically acceptable salt thereof, in an amountsufficient to deliver 15 mg of upadacitinib freebase equivalent, whereinthe subject achieves a Psoriasis Area Severity Index (PAST) 75 responsewithin 16 weeks of administration of the first dose (including at week16). In certain embodiments, the subject achieves a PASI 90 responsewithin 16 weeks of administration of the first dose (including at week16). In certain embodiments, the subject achieves a PASI 100 responsewithin 16 weeks of administration of the first dose (including at week16). In certain embodiments, the PAST response (e.g., the PASI 75, PASI90, and/or PASI 100 response) is maintained or improved after week 16 bycontinuing to administer a daily dose of the upadacitinib freebase, or apharmaceutically acceptable salt thereof. In one aspect, the subject isnon-biologic DMARD-IR. In one aspect, the subject is bDMARD-IR.

In yet other aspects, provided is a method of treating active PsA in asubject in need thereof, the method comprising orally administering tothe subject once a day for at least 16 weeks a dose of upadacitinibfreebase, or a pharmaceutically acceptable salt thereof, in an amountsufficient to deliver 30 mg of upadacitinib freebase equivalent, whereinthe subject achieves a Psoriasis Area Severity Index (PAST) 75 responsewithin 16 weeks of administration of the first dose (including at week16). In certain embodiments, the subject achieves a PASI 90 responsewithin 16 weeks of administration of the first dose (including at week16). In certain embodiments, the subject achieves a PASI 100 responsewithin 16 weeks of administration of the first dose (including at week16). In certain embodiments, the PAST response (e.g., the PASI 75, PASI90, and/or PASI 100 response) is maintained or improved after week 16 bycontinuing to administer a daily dose of the upadacitinib freebase, or apharmaceutically acceptable salt thereof. In one aspect, the subject isnon-biologic DMARD-IR. In one aspect, the subject is bDMARD-IR.

In yet another aspect, provided is a method of treating active PsA in apopulation of subjects in need thereof, the method comprisingadministering a dose of upadacitinib freebase, or a pharmaceuticallyacceptable salt thereof, to the subjects according to the methodsdescribed herein, wherein a portion of the subjects in the treatedpopulation (e.g., a statistically significant population of the subjectsin the treated population and/or at least 10%, at least 15%, at least20°/o, at least 25%, at least 30%, at least 35%, at least 40%, or atleast 45% of the subjects in the treated population) achieve a PAST 75response within 16 weeks of administration of the first dose (includingat week 16). In certain embodiments, subjects in the treated populationachieve a PASI 90 response within 16 weeks of administration of thefirst dose (including at week 16). In certain embodiments, subjects inthe treated population achieve a PASI 100 response within 16 weeks ofadministration of the first dose (including at week 16). In certainembodiments, the PASI response (e.g., the PASI 75, PASI 90, and/or PASI100 response) is maintained or improved after week 16 by continuing toadminister a daily dose of the JAK1 inhibitor. In one aspect, theupadacitinib freebase, or a pharmaceutically acceptable salt thereof, isadministered in an amount sufficient to deliver 15 mg of upadacitinibfreebase equivalent. In one aspect, the upadacitinib freebase, or apharmaceutically acceptable salt thereof, is administered in an amountsufficient to deliver 30 mg of upadacitinib freebase equivalent. In oneaspect, the upadacitinib freebase, or a pharmaceutically acceptable saltthereof, is administered orally once a day for at least 16 weeks. In oneaspect, the subjects in the treated population are non-biologic DMARD-IRat baseline. In one aspect, the subject in the treated population arebDMARD-IR at baseline.

In certain embodiments, the subject (or subjects in the treatedpopulation) with active PsA at baseline is an adult subject. In anotheraspect, the subject (or subjects in the treated population) with activePsA at baseline is a juvenile subject. In certain embodiments, thesubject (or subjects in the treated population) has >3% Body SurfaceArea with Psoriasis at baseline.

Further provided are methods of treating psoriasis (PsO), including PsOas a skin manifestation of PsA.

For example, in one aspect, provided is a method of treating activepsoriasis in a subject in need thereof, the method comprising orallyadministering to the subject once a day for at least 16 weeks a dose ofupadacitinib freebase, or a pharmaceutically acceptable salt thereof, inan amount sufficient to deliver 15 mg of upadacitinib freebaseequivalent, wherein the subject achieves a Psoriasis Area Severity Index(PAST) 75 response within 16 weeks of administration of the first dose(including at week 16). In certain embodiments, the subject achieves aPASI 90 response within 16 weeks of administration of the first dose(including at week 16). In certain embodiments, the subject achieves aPAST 100 response within 16 weeks of administration of the first dose(including at week 16). In certain embodiments, the PASI response (e.g.,PASI 75, PASI 90, or PASI 100 response) is maintained or improved afterWeek 16 by continuing to administer a daily dose of the upadacitinibfreebase, or a pharmaceutically acceptable salt thereof.

In yet other aspects, provided is a method of treating active psoriasisin a subject in need thereof, the method comprising orally administeringto the subject once a day for at least 16 weeks a dose of upadacitinibfreebase, or a pharmaceutically acceptable salt thereof, in an amountsufficient to deliver 30 mg of upadacitinib freebase equivalent, whereinthe subject achieves a Psoriasis Area Severity Index (PAST) 75 responsewithin 16 weeks of administration of the first dose (including at week16). In certain embodiments, the subject achieves a PASI 90 responsewithin 16 weeks of administration of the first dose (including at week16). In certain embodiments, the subject achieves a PASI 100 responsewithin 16 weeks of administration of the first dose (including at week16). In certain embodiments, the PAST response (e.g., PASI 75, PASI 90,or PASI 100 response) is maintained or improved after Week 16 bycontinuing to administer the daily dose of the upadacitinib freebase, ora pharmaceutically acceptable salt thereof.

In yet another aspect, provided is a method of treating active psoriasisin a population of subjects in need thereof, the method comprisingadministering a dose of upadacitinib freebase, or a pharmaceuticallyacceptable salt thereof, to the subjects according to the above methods,wherein a portion of the subjects in the treated population (e.g., astatistically significant population of the subjects in the treatedpopulation and/or at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, or at least 45% of thesubjects in the treated population) achieve a PASI 75 response within 16weeks of administration of the first dose (including at week 16). Incertain embodiments, subjects in the treated population achieve a PASI90 response within 16 weeks of administration of the first dose(including at week 16). In certain embodiments, subjects in the treatedpopulation achieve a PASI 100 response within 16 weeks of administrationof the first dose (including at week 16). In certain embodiments, thePASI response (e.g., PASI 75, PASI 90, or PASI 100 response) ismaintained or improved after Week 16 by continuing to administer thedaily dose of the upadacitinib freebase, or a pharmaceuticallyacceptable salt thereof. In one aspect, the upadacitinib freebase, or apharmaceutically acceptable salt thereof, is administered in an amountsufficient to deliver 15 mg of upadacitinib freebase equivalent. In oneaspect, the upadacitinib freebase, or a pharmaceutically acceptable saltthereof, is administered in an amount sufficient to deliver 30 mg ofupadacitinib freebase equivalent. In one aspect, the upadacitinibfreebase, or a pharmaceutically acceptable salt thereof, is administeredorally once a day for at least 16 weeks. In one aspect, the subjects inthe treated population are non-biologic DMARD-IR at baseline. In oneaspect, the subject in the treated population are bDMARD-IR at baseline.

In certain embodiments, the subject (or subjects in the treatedpopulation) with active psoriasis at baseline is an adult subject. Inanother aspect, the subject (or subjects in the treated population) withactive psoriasis at baseline is a juvenile subject. In certainembodiments, the subject (or subjects in the treated population) has >3%Body Surface Area with Psoriasis at baseline.

In certain embodiments, the active psoriasis is a skin manifestation ofPsA. For example, in certain embodiments, the subject (or subjects inthe treated population) in need thereof have active PsA.

EXAMPLES Examples 1-4: Extended Release Tablets

The Freebase Hydrate Form C and Amorphous Freebase solid state forms ofCompound 1 were formulated into 24 mg extended release tablets accordingto the formulations set forth in Table 6.

TABLE 6 Extended Release Tablets (no pH modifier) Ex. 1 Ex. 2 Ex .3(ER1) (ER2) (ER3) Ex. 4 Component Function (mg) (mg) (mg) (mg) FreebaseHydrate Form C Active 24.0 24.0 24.0 — Amorphous Freebase Active — — —24.0 Microcrystalline cellulose Filler 351.4 303.4 303.4 303.4(Avicerl ® PH 102) HPMC (Methocel ® K100 Release control 96.0 96.0 — —Premium LVCRLH) polymer HPMC (Methocel ® K4M Release control — 48.0144.0 144.0 Premium CR) polymer Colloidal silicon dioxide Glidant 3.83.8 3.8 3.8 Magnesium stearate Lubricant 4.8 4.8 4.8 4.8 impalpablepowder Uncoated weight of tablet 480.0 480.0 480.0 480.0

The formulations were prepared by combining and blending the active,microcrystalline cellulose, hydroxypropyl methyl cellulose (HPMC), andcolloidal silicone dioxide. The blend was milled using a Mobil Millfitted with a 610-micron screen. The magnesium stearate was screenedthrough mesh #30 and was added to the bin and blended.

The lubricated granulation was compressed into 480 mg weight tabletsusing a rotary tablet press. The tablets may optionally be coated withany suitable film coating.

The effect of solid state form on the dissolution profile of the tabletswas evaluated. In particular, the dissolution profile of the Example 3(containing Freebase Hydrate Form C as active) and Example 4 (containingAmorphous Freebase as active) tablets was evaluated at pH 6.8(representative of the pH in the lower intestine). The dissolution testwas carried out using the following dissolution parameters andconditions:

-   -   Apparatus: USP Dissolution Apparatus 2 and fraction collector    -   Medium: 900 mL of 50 mM sodium phosphate buffer solution, pH        6.8.    -   Temperature: 37° C.±0.5° C.    -   RPM: 75 RPM±4%    -   Filter: 35 μm PE filter, or equivalent, for automatic sampling    -   Sampling Times: 1, 2, 4, 6, 8, 10, 12, 16, and 20 Hours.        -   Other samples may be taken at other times, as appropriate.    -   Sample Volume: 1.5 mL obtained automatically, without media        replacement.

The medium used for the study was a 0.05 M sodium phosphate buffersolution, pH 6.8 f 0.05. The medium was prepared using an acid stagemedium (0.1 N hydrochloric acid solution) and a buffer stage concentrate(0.05 M sodium phosphate buffer concentrate solution, prepared bydissolving about 41.4 g of sodium phosphate, monobasic, monohydrate andabout 14.4 g of sodium hydroxide pellets in about 4 L of water, diluteto 6 L with water and mixing well). The medium was prepared by mixing500 mL of the acid stage medium and 400 mL of buffer stage concentratein an appropriate size container or directly in the dissolution vesseland adjusting the pH with 1 N phosphoric acid or 1 N sodium hydroxide,if the pH was not within 6.8±0.05.

For the dissolution test, one tablet each was added to a dissolutionvessel containing 900 mL of the 0.05 M sodium phosphate buffer solutionmaintained at 37° C. The paddles of the dissolution apparatus wereoperated at 75 RPM, with 1.5 mL samples from the dissolution vesselautomatically obtained at the designated time periods. The samplefiltrate was the sample preparation.

-   -   For the analysis of the sample, conventional liquid        chromatography methods were utilized, wherein the % of the        labelled amount of active released (% LA Released) was        calculated. The formulation containing Freebase Hydrate Form C        (Example 3) as the active showed a slower rate of dissolution        than the formulation containing Amorphous Freebase (Example 4)        as the active at pH 6.8.

The dissolution profile of formulations comprising Freebase Hydrate FormC as an active was further evaluated at pH 6.8 and in a dual pH system.In particular, the dissolution profile of the Example 1 (ER1), Example 2(ER2), and Example 3 (ER3) tablets at pH 6.8 was carried out asdescribed above. The dissolution profile of the Examples 1-3 tablets wasalso carried out in a dual pH system using the following dissolutionparameters and conditions:

-   -   Apparatus: USP Dissolution Apparatus 2 and fraction collector    -   Medium: Acid Stage: 500 mL of Acid Stage Medium (0.1 N        hydrochloric acid solution)        -   Buffer Stage: 900 mL of 50 mM sodium phosphate buffer            solution, pH 6.8.    -   Temperature: 37° C.±0.5° C.    -   RPM: 75 RPM±4%    -   Filter: 35 μm PE filter, or equivalent, for automatic sampling    -   Sampling Times: Acid Stage: 1 Hour    -   Buffer Stage: 2, 4, 6, 8, 10, 12, 16, and 20 Hours.        -   Other samples may be taken at other times, as appropriate.    -   Sample Volume: Acid: 1.5 mL obtained automatically, without        media replacement.

The acid stage medium is a 0.1 N hydrochloric acid solution. A bufferstage medium for the study was prepared using a buffer stage concentrate(0.05 M sodium phosphate buffer concentrate solution, prepared bydissolving about 41.4 g of sodium phosphate, monobasic, monohydrate andabout 14.4 g of sodium hydroxide pellets in about 4 L of water, diluteto 6 L with water and mixing well). The buffer stage medium of a 0.05 Msodium phosphate buffer solution, pH 6.8±0.05, was prepared by mixing500 mL of the acid stage medium and 400 mL of buffer stage mediumconcentrate in an appropriate size container or directly in thedissolution vessel and adjusting the pH of the buffer stage mediumconcentrate with 1 N phosphoric acid or 1 N sodium hydroxide, if the pHwas not within 6.8±0.05.

For the dissolution test, one tablet each was added to a dissolutionvessel containing 500 mL of a 0.1 N hydrochloric acid solutionmaintained at 37° C. The paddles of the dissolution apparatus wereoperated at 75 RPM for 1 hour, and then a 1.5 mL sample from thedissolution vessel was automatically obtained. After the acid stagesample was obtained, 400 mL of buffer stage medium concentrate wasadded, maintained at 37° C. The dissolution test was continued, with thepaddles remaining at a speed of 75 RPM. The sample filtrate was thesample preparation.

For the analysis of the sample, conventional liquid chromatographymethods were utilized, wherein the % relative standard deviation (RSD)of peak areas was calculated for each set of six standard injections.

After the initial release at the low pH (representative of the pH in thestomach), release of the drug is slowed at the higher pH (representativeof the pH in the lower intestine). Therefore, in order to achieve thedesired bioavailability, a formulation which allowed pH independentrelease was required.

Examples 5-12: Extended Release Tablets

The Freebase Hydrate Form C solid state form of Compound 1 wasformulated into 15 mg, 24 mg, or 30 mg extended release tabletsaccording to the formulations set forth in Table 7 using directcompression.

TABLE 7 Extended Release Tablets (tartaric acid pH modifier) Ex. 10 Ex.5 Ex. 8 Ex. 9 (mg) Ex. 11 Ex. 12 (mg) Ex. 6 Ex. 7 (mg) (mg) (ER4, no(mg) (mg) Component Function (ER7) (mg) (mg) (ER8) (ER4) mannitol) (ER5)(ER6) Freebase Active 15.4^(a) 15.4^(a) 15.4^(a) 30.7^(b) 24.6^(c)24.6^(c) 24.6^(c) 24.6^(c) Hydrate Form C Microcrystalline Filler 162.4162.4 162.4 147.1 158.0 210.6 282.6 258.6 cellulose (Avicel ® PH 102)Mannitol Filler 52.6 52.4 — 52.6 52.7 — — — (Pearlitol ® 100 SD)Mannitol Filler — — 52.4 — — — — — (Pearlitol ® 200 SD) Tartaric acid pH144.0 144.0 144.0 144.0 144.0 144.0 96.0 96.0 modifier HPMC Release 96.0— — 96.0 — — — (Hypromellose control 2208) polymer HPMC Release — 96.096.0 — 96.0 96.0 — — (Methocel ® control K4M Premium polymer CR)Carbopol ® 71G Release — — — — — 48.0 72.1 control polymer Carbopol ®Release — — — — — 24.0 24.0 971P control polymer Colloidal siliconGlidant 2.4 2.4 2.4 2.4 — — — — dioxide Magnesium Lubricant 7.2 7.2 7.27.2 4.8 4.8 4.8 4.8 stearate impalpable powder Uncoated weight of tablet480.0 479.8 479.8 480.0 480.1 480.0 480.0 480.1 Opadry ® II Film coat14.40 — — 14.40 — — — — Yellow (PVA based) Total weight of tablet 494.39494.43 — — — — ^(a)Provides 15 mg of Compound 1 freebase equivalent.^(b)Provides 30 mg of Compound 1 freebase equivalent. ^(c)Provides 24 mgof Compound 1 freebase equivalent.

The formulations were prepared by first milling the tartaric acidthrough a Fitz mill Model MSA, fitted with a 1512-0027 screen. TheFreebase Hydrate Form C, microcrystalline cellulose, mannitol (whenpresent), milled tartaric acid, release control polymer, and colloidalsilicone dioxide (when present) were combined and blended. The blend wasmilled using a Mobil Mill fitted with a 610- or 1397-micron screen. Themagnesium stearate was screened through mesh #30 and was then added tothe bin and blended. The lubricated granulation was compressed intoabout 480 mg weight tablets using a rotary tablet press.

The Example 5 and 8 tablets were coated using a film coater, whichsprayed a solution containing the Opadry® II Yellow film coat andpurified water until 14.40 mg of coating had been applied to thetablets.

The dissolution profile of the Example 9 (ER4, 24 mg active), Example 10(ER4, no mannitol, 24 mg active), Example 11 (ERS, 24 mg active), andExample 12 (ER6, 24 mg active) tablets was evaluated at pH 1.2, at pH6.8, and in a dual pH system. The pH 6.8 study was performed asdescribed above for Examples 3 and 4. For the dual pH study, an acidstage medium of 0.05 M sodium phosphate solution, pH 3.5 t 0.05, wasprepared by dissolving about 41.4 g of sodium phosphate, monobasic,monohydrate in about 4 L of water, measuring the pH and addingphosphoric acid, 85%, dropwise as needed to adjust to the target pH. Themixture was diluted to 6 L with water and mixed. A buffer stage mediumfor the study was prepared using a buffer stage concentrate (0.05 Msodium phosphate buffer concentrate solution, prepared by dissolvingabout 41.4 g of sodium phosphate, monobasic, monohydrate and about 14.4g of sodium hydroxide pellets in about 4 L of water, dilute to 6 L withwater and mixing well). The buffer stage medium of a 0.05 M sodiumphosphate buffer solution, pH 6.8 t 0.05, was prepared by mixing 500 mLof the acid stage medium and 400 mL of buffer stage medium concentratein an appropriate size container or directly in the dissolution vesseland adjusting the pH of the buffer stage medium concentrate with 1 Nphosphoric acid or 1 N sodium hydroxide, if the pH was not within6.8±0.05.

The dissolution test was carried out using the following dissolutionparameters and conditions:

-   -   Apparatus: USP Dissolution Apparatus 2 and fraction collector    -   Medium: Acid Stage: 500 mL of Acid Stage Medium    -   Buffer Stage: 900 mL of 50 mM sodium phosphate buffer solution,        pH 6.8    -   Temperature: 37° C.±0.5° C.    -   RPM: 75 RPM±4%    -   Filter: 35 μm PE filter, or equivalent, for automatic sampling    -   Sampling Times: Acid Stage: 1 Hour        -   Buffer Stage: 2, 4, 6, 8, 10, 12, 16, and 20 Hours.        -   Other samples may be taken at other times, as appropriate.    -   Sample Volume: Acid and Buffer Stage: 1.5 mL obtained        automatically, without media replacement.

For the dissolution test, one tablet each was added to a dissolutionvessel containing 500 mL of the acid stage medium, maintained at 37° C.The paddles of the dissolution apparatus were operated at 75 RPM for 1hour, and then a 1.5 mL sample from the dissolution vessel wasautomatically obtained. After the acid stage sample was obtained, 400 mLof buffer stage medium concentrate was added, and then the mixture wasmaintained at 37° C. The dissolution test was continued, with thepaddles remaining at a speed of 75 RPM. The sample filtrate was thesample preparation.

For the pH 1.2 study, the dissolution test was carried out using thefollowing dissolution parameters and conditions:

-   -   Apparatus: USP Dissolution Apparatus 2 and fraction collector    -   Medium: 500 mL of Acidic Medium, pH 1.2    -   Temperature: 37° C.±0.5° C.    -   RPM: 75 RPM±4%    -   Filter: 35 μm PE filter, or equivalent, for automatic sampling    -   Sampling Times: 1, 2, 4, 6, 8, 10, 12, 16, and 20 Hours.        -   Other samples may be taken at other times, as appropriate.    -   Sample Volume: 1.5 mL obtained automatically, without media        replacement.

For this study, an acidic medium of 0.05 M sodium phosphate solution, pH3.5 f 0.05, was prepared by dissolving about 41.4 g of sodium phosphate,monobasic, monohydrate in about 4 L of water, measuring the pH andadding phosphoric acid, 85%, dropwise as needed to adjust to the targetpH of 1.2. The mixture was diluted to 6 L with water and mixed.

For the dissolution test, one tablet each was added to a dissolutionvessel containing 500 mL of the acidic medium, maintained at 37° C. Thepaddles of the dissolution apparatus were operated at 75 RPM, with 1.5mL samples from the dissolution vessel automatically obtained at thedesignated time periods. The sample filtrate was the sample preparation.

For the analysis of the sample, conventional liquid chromatographymethods were utilized, wherein the % relative standard deviation (RSD)of peak areas was calculated for each set of six standard injections.The results shown that pH independence is achieved in the once dailyformulations.

The dissolution profile of the Example 5 (ER7), Example 8 (ER8), andExample 9 (ER4) tablets were evaluated in a dual pH system, as describedabove. The formulations provide an extended release profile of 80-100%over a period of about 8-10 hours.

The formulations of Examples 5 and 8-12 all exhibited pH independentrelease of the active ingredient. In contrast, after the initial releaseat the low pH, release of the active is slowed at the higher pH for theformulations of Examples 1-3. Without wishing to be bound to anyparticular theory, it is believed that the inclusion of tartaric acid asa pH modifier in the Example 5 and 8-12 formulations contributed to thepH independent release observed for these tablets.

Example 13: Extended Release Tablet

The Freebase Hydrate Form C solid state form of Compound 1 wasformulated into a 7.5 mg extended release tablet according to theformulation set forth in Table 8.

TABLE 8 Extended Release Tablet (tartaric acid pH modifier) Ex. 34 (mg)Component Function (ER9) Freebase Hydrate Form C* Active   7.678^(a)Microcrystalline cellulose Filler 170.1   (Avicel ® PH 102) Mannitol(Pearlitol ® 100 SD) Filler  52.62 Tartaric acid (crystalline) pHmodifier 144.0  HPMC (Hypromellose 2208) Release control 96.0  polymerColloidal silicon dioxide Glidara 2.4 Magnesium stearate Lubricant 7.2Uncoated weight of tablet 479.998 Opadry ® II Yellow Film coat 14.40Purified water Processing aid n/a Total weight of tablet 494.398^(a)Provides 7.5 mg of Compound 1 freebase equivalent.

The formulation was prepared by first milling the tartaric acid througha Fitz mill Model M5A, fitted with a 1512-0027 screen. The FreebaseHydrate Form C, microcrystalline cellulose, mannitol, milled tartaricacid, release control polymer, and colloidal silicone dioxide werecombined and blended. The blend was milled using a Mobil Mill fittedwith a 610-micron screen. The magnesium stearate was screened throughmesh #30 and was then added to the bin and blended. The lubricatedgranulation was compressed into about 480 mg weight tablets using arotary tablet press.

The tablets were coated using a film coater, which sprayed a solutioncontaining the Opadry® II Yellow film coat and purified water until 14.4mg of coating had been applied to the tablets.

Examples 14-19: Extended Release Tablets

The Freebase Hydrate Form C solid state form of Compound 1 wasformulated into 15 mg or 30 mg extended release tablets according to theformulations set forth in Table 9. The tablets were prepared using a wetgranulation process, and were compressed into tablets having a coreweight of about 480 mg.

TABLE 9 Extended Release Tablets (tartaric acid pH modifier) Ex. 14 Ex.15 Ex. 16 Ex. 17 Ex. 18 Ex. 19 (mg) (mg) (mg) (mg) (mg) (mg) ComponentFunction (ER10) (ER11) (ER12) (ER13) (ER14) (ER15) Tablet Core(Intragranular) Freebase Hydrate Form C Active 30.7^(a) 30.7^(a)30.7^(a) 15.4^(b) 15.4^(b) 15.4^(b) Microcrystalline cellulose Filler79.9 79.9 79.9 40.0 40.0 40.0 (Avicel ® PH 101) HPMC (HypromelloseRelease control 9.5 9.5 9.5 4.8 4.8 4.8 2208) polymer Tablet Core(Extragranular) Microcrystalline cellulose Filler 67.2 67.2 67.2 122.5122.5 122.5 (Avicel ® PH 102) Mannitol Filler 52.6 100.6 148.6 52.6100.6 148.6 Tartaric acid (crystalline) pH modifier 144.0 96.0 48.0144.0 96.0 48.0 HPMC (Hypromellose Release control 86.5 86.5 86.5 91.291.2 91.2 2208) polymer Colloidal silicon Glidant 2.4 2.4 2.4 2.4 2.42.4 dioxide/silica Magnesium stearate Lubricant 7.2 7.2 7.2 7.2 7.2 7.2Uncoated weight of tablet 480.0 480.0 480.0 480.1 480.1 480.1 Opadry ®II Yellow^(c) Film coat 14.4 14.4 14.4 14.4 14.4 14.4 Total weight oftablet 494.4 494.4 494.4 494.5 494.5 494.5 ^(a)Provides 30 mg ofCompound 1 freebase equivalent. ^(b)Provides 15 mg of Compound 1free-base equivalent. ^(c)Film coat weight is approximate.

The formulation was prepared by first milling the tartaric acid througha Fitz mill Model MSA, fitted with a 1512-0027 screen. The intragranularportion of the hydroxypropylmethyl cellulose release control polymer,the Freebase Hydrate Form C, and intragranular portion of themicrocrystalline cellulose filler were added to a granulator, and mixed.Water was sprayed to granulate. The granulated material was then driedand milled using a comill fitted with a 610-micron screen. The milledgranulation was then added to the extragranular tablet components otherthan magnesium stearate, and sieved using a comill fitted with a1397-micron screen, followed by blending. The magnesium stearate wasthen added to the bin and blended. The lubricated granulation wascompressed into about 480 mg weight tablets using a rotary tablet press.

The tablets were coated using a film coater, which sprayed a solutioncontaining the Opadry® II Yellow film coat and purified water until 14.4mg of coating had been applied to the tablets.

Example 20: Evaluation of the Effect of Organic Acids on DissolutionProfile of Extended Release Tablets

In this example, the effect of various organic acid pH modifiers (e.g.,tartaric acid, citric acid, succinic acid, and fumaric acid) on therelease rate of Freebase Hydrate Form C from 24 mg once-daily extendedrelease (ER) tablets was evaluated. Freebase Hydrate Form C wasformulated into 24 mg extended release tablets according to theformulations set forth in Table 10.

TABLE 10 Extended Release Tablets Tartaric Acid Citric acid Succinicacid Fumaric acid Component Function A B C D E F G H Freebase HydrateActive 24.6 24.6 24.6 24.6 24.6 24.6 24.6 24.6 Form C MicrocrystallineFiller 306.6 306.6 306.6 306.6 306.6 306.6 306.6 306.6 cellulose(Avicel ® PH102) HPMC Release 96.0 — 96.0 — 96.0 — 96.0 — (Methocel ®K4M) control polymer Carbopol ® 71G Release — 96.0 — 96.0 — 96.0 — 96.0control polymer Organic acid pH 48.0 48.0 48.0 48.0 48.0 48.0 48.0 48.0modifier Magnesium Lubricant 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 stearateTotal 480.0 480.0 480.0 480.0 480.0 480.0 480.0 480.0

The formulations were prepared by first milling the organic acid througha Fitz mill Model M5A, fitted with a 1512-0027 screen. The active,microcrystalline cellulose, milled organic acid, and release controlpolymer, were combined and blended. The blend was milled using a MobilMill fitted with a 610-micron screen. The magnesium stearate wasscreened through mesh #30 and was added to the bin and blended. Thelubricated granulation was compressed into 480 mg weight tablets using arotary tablet press.

The effect of the organic acids on the dissolution profile of thetablets was evaluated at pH 1.2 and pH 6.8. The dissolution tests werecarried out using the dissolution parameters and conditions as describedabove in Examples 3 and 4 and 9-12. For analysis of the sample,conventional liquid chromatography methods were utilized, wherein the %of the labelled amount of active released (% LA Released) wascalculated. The results show that organic acids improved dissolutionrate at high pH, with tartaric acid showing the best improvement. Theformulations comprising the control release polymer Carbopol® withtartaric acid provided near linear release at pH 6.8.

Example 21: Gel pH Measurements for Tablets with Different Amounts ofTartaric Acid

To measure the pH of the environment created when Compound 1 reacts withHPMC, the following experiment was performed.

The Freebase Hydrate Form C solid state form of Compound 1 wasformulated into 30 mg extended release tablets according to theformulations set forth in Table 11A. The tablets were prepared using awet granulation process, as described in Examples 14-19.

Dissolution media of 0.01 N HCl (pH 2) and 113 mM sodium phosphatebuffer (pH 6.8) was prepared at 37° C. One tablet was added to 500 mL of0.01 N HC media and stirred at 75 rpm at 37° C. for one hour in a VankelVK 7010 dissolution bath. Then 400 mL of sodium phosphate buffer wasadded. The solution was stirred an additional three hours. The tabletwas removed, rinsed with water and dried using laboratory tissues. Thegel that formed on the tablet was separated from the dry core for pHmeasurement. This procedure was repeated three tines for eachformulation. The pH of the gel formed on the tablets is set forth inTable 11B.

TABLE 11A Formations Formulation Formulation Formulation FormulationFormulation Component 1 2 3 4 5 Intragranular mg/tab mg/tab mg/tabmg/tab mg/tab Freebase 30.71 30.71 30.71 30.71 30.71 Hydrate Form C HPMC3.920 3.920 3.920 3.920 3.920 (Methocel ® K4M) Microcrystalline 30.7130.71 30.71 30.71 30.71 cellulose (Avicel ® PH102) extragranularMicrocrystalline 116.4 164.4 188.4 212.4 260.4 cellulose (Avicel ®PH102) Tartaric Acid 144.0 96.00 72.00 48.00 0.00 (milled) Mannitol52.62 52.62 57.67 52.62 52.62 (Pearlitol ® 100SD) HPMC 92.08 92.08 92.0892.08 92.08 (Methocel ® K4M) Colloidal 2.400 2.400 2.400 2.400 2.400silicon dioxide Magnesium 7.200 7.200 7.200 7.200 7.200 Stearate Total480.04 480.04 480.04 480.04 480.04

TABLE 11B pH Results % Tartaric Formulation Acid 1^(st) tablet 2^(nd)tablet 3^(rd) tablet Average 1 30 2.63 2.68 2.81 2.71 2 20 3.17 3.093.23 3.16 3 15 3.42 3.94 3.65 3.67 4 10 3.88 3.67 3.77 3.77 5 0 6.266.21 6.55 6.34

Example 22: Evaluation of the In Vivo Pharmacokinetic Profile of 15 mgExtended Release Tablets (Fasting)

The pharmacokinetic profile of the 15 mg once-daily extended release(ER) tablets prepared in Example 5 was evaluated, and compared to thatof a 12 mg immediate-release (IR) capsule comprising Tartrate Hydrate asthe active.

-   -   Healthy human subjects (n=11) were administered a single dose of        the 12 mg IR capsule (Regimen A) and the 15 mg ER (once-daily)        tablet from Example 5 (Regimen B) under fasting conditions in a        randomized, two-period, cross-over study design. Subjects were        administered Regimen A in the first study period and Regimen B        in the second study period, or administered Regimen B in the        first study period and Regimen A in the second study period.        Serial blood samples were collected from each subject prior to        dosing and for 72 hours after dosing in each study period. Upon        collection, the samples were promptly placed in an ice bath, and        within 2 hours after sample collection they were centrifuged at        about 4° C. The resulting plasma samples were placed in clean        polypropylene-tubes and stored in a freezer until analysis. The        plasma samples were assayed for Compound 1 using appropriate        liquid chromatography mass spectrometry procedures.    -   Pharmacokinetic parameters were estimated using        non-compartmental methods, and summary statistics were computed        for each parameter by regimen. The results are summarized in        Table 12A.

TABLE 12A Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of 15 mg ER Tablet and 12 mg IR CapsuleFormulations Under Fasting Conditions Regimen A Regimen B PK ParameterUnits (IR Capsule, 12 mg) (ER Tablet, 15 mg) C_(max) ng/mL 64.6 (16)26.0 (37) T_(max) ^(a) hours     1.0 (0.5-1.5)    3.0 (1.0-40) t_(1/2)^(b) hours  9.2 (119) 12.5 (90) AUC_(t) ng · h/mL  231 (15)  227 (26)AUC_(inf) ng · h/mL  234 (15)  242 (26) ^(a)Median (minimum, maximum)^(b)Harmonic mean (pseudo-% CV) ^(c)Data in parentheses is coefficientof variance of the PK parameter (% CV), unless otherwise indicated.

As can be seen from this data, the 15 mg ER tablet provided a lowerC_(max) and comparable AUC to the 12 mg IR capsule under fastingconditions.

The relative bioavailability for a single dose of the once-daily (ER)tablet formulation (Regimen B) relative to the IR capsule formulation(Regimen A) was also determined based on analysis of the naturallogarithms of C_(max) and AUC. The results are summarized in Table 12Bbelow.

TABLE 12B Relative Bioavailability and 90% Confidence Intervals forBioequivalence Assessment Relative Bioavailability 90% Confidence PKParameter Point Estimate Interval C_(max) 0.373 0.312-0.446 AUC_(t)0.939 0.869-1.013 AUC_(inf) 0.992 0.909-1.082

For Regimen B versus Regimen A, the point estimates for the ratios ofAUC_(t) and AUC_(inf) were near unity, and the 90% confidence intervalswere within the 0.86-1.09 range.

Example 23: Evaluation of the In Vivo Pharmacokinetic Profile of 30 mgExtended Release Tablets (Fasting)

The pharmacokinetic profile of the 30 mg once daily extended release(ER) tablets prepared in Example 8 was evaluated, and compared to thatof a 24 mg dose of an immediate release (IR) capsule comprising TartrateHydrate as the active.

-   -   Healthy human subjects (n=12) were administered a single 24 mg        dose (two 12 mg IR capsules) (Regimen C) and the 30 mg ER (once        daily) tablet from Example 8 (Regimen D) under fasting        conditions in a randomized, two-period, cross-over study design.        Half the subjects were administered Regimen C in the first study        period and Regimen D in the second study period, while the other        half were administered Regimen D in the first study period and        Regimen C in the second study period. Serial blood samples were        collected from each subject prior to dosing and for 72 hours        after dosing in each study period. Upon collection, the samples        were promptly placed in an ice bath, and within 2 hours after        sample collection they were centrifuged at about 4° C. The        resulting plasma samples were placed in clean        polypropylene-tubes and stored in a freezer until analysis. The        plasma samples were assayed for Compound 1 using appropriate        liquid chromatography mass spectrometry procedures.        Pharmacokinetic parameters were estimated using        non-compartmental methods, and summary statistics were computed        for each parameter by regimen. The results are summarized in        Table 13A.

TABLE 13A Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of 30 mg ER Tablet and 24 mg Dose (2 × 12 mg)IR Capsule Formulations Under Fasting Conditions Regimen C Regimen D PKParameter Units (IR Capsules, 24 mg) (ER Tablet, 30 mg) C_(max) ng/mL176 (37) 63.7 (33)  T_(max) ^(a) hours     0.5 (0.5-1.5)   2.0 (1.5−4,0)t_(1/2) ^(b) hours  9.9 (52) 10.8 (67)  AUC_(t) ng · h/mL 520 (25) 477(27) AUC_(inf) ng · h/mL 524 (25) 491 (27) ^(a)Median (minimum-maximum)^(b)Harmonic mean (pseudo % CV)

-   -   ^(c)—Data in parentheses is the coefficient of variance of the        PK parameter (% CV), unless otherwise indicated.

As can be seen from this data, the 30 mg ER tablet provided a lowerC_(max) and comparable AUC to the 24 mg dose IR capsule (2×12 mg) underfasting conditions.

The relative bioavailability for a single dose of the once-daily (ER)tablet formulation (Regimen D) relative to the IR capsule formulations(Regimen C) was also determined based on analysis of the naturallogarithms of C_(max) and AUC. The results are summarized in Table 13Bbelow.

TABLE 13B Relative Bioavailability and 90% Confidence Intervals forBioequivalence Assessment PK Value Relative Bioavailability Regimen C90% Confidence PK Paramenter Regimen D (reference) Point EstimateInterval C_(max) 63.7 176 0.368 0.326-0.415 AUC_(t) 477 520 0.9120.828-1.004 AUC_(inf) 491 524 0.933 0.845-1.029

For Regimen D versus Regimen C, the point estimates for the ratios ofAUC_(t) and AUC_(inf) were near unity, and the 90% confidence intervalswere within the 0.82-1.03 range.

Example 24: Comparison of the In Vivo Pharmacokinetic Profile of 30 mgExtended Release Tablets Under Fasting Versus Fed Conditions

The pharmacokinetic profile of the 30 mg extended release tabletsprepared in Example 8 after a high-fat meal was evaluated, and comparedto the pharmacokinetic profile of the 30 mg extended release tabletsunder fasting conditions (see Example 23).

-   -   Following completion of the Example 23 study, the healthy human        subjects (n=12) were administered single doses of the 30 mg ER        (once daily) tablet from Example 8 after a high-fat meal        (Regimen E). Serial blood samples were collected from each        subject prior to dosing and for 72 hours after dosing. Upon        collection, the samples were promptly placed in an ice bath, and        within 2 hours after sample collection they were centrifuged at        about 4° C. The resulting plasma samples were placed in clean        polypropylene-tubes and stored in a freezer until analysis. The        plasma samples were assayed for Compound 1 using appropriate        liquid chromatography mass spectrometry procedures.        Pharmacokinetic parameters were estimated using        non-compartmental methods, and summary statistics were computed        for each parameter, and compared to the pharmacokinetic        parameters for the 30 mg tablets administered under fasting        conditions (see Example 23, Regimen D). The results are        summarized in Table 14A.

TABLE 14A Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of 30 mg ER Tablet Under Fasting Conditions orAfter a High-Fat Meal Regimen E Regimen D (After High-Fat PK ParameterUnits (Fasting) Meal) C_(max) ng/mL 63.7 (33) 76.8 (39) T_(max) ^(a)hours    2.0 (1.5-4.0)    4.0 (1.5-8.0) t_(1/2) ^(b) hours  0.8 (67)11.9 (51) AUC_(t) ng · h/mL  477 (27) 564 (26) AUC_(inf) ng · h/mL  491(27) 577 (27) ^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-CV%) ^(c)Data in parentheses is coefficient of variance of the PKparameter (% CV), unless otherwise indicated.

The relative bioavailability for a single dose of the once-daily (ER) 30mg tablet formulation after a high-fat meal (Regimen E) relative to thebioavailability of the ER 30 mg tablet under fasting conditions (RegimenD) was also determined based on analysis of the natural logarithms ofC_(max) and AUC. The results are summarized in Table 14B below.

TABLE 14B Relative Bioavailability, and 90% Confidence Intervals forBioequivalence Assessment PK Value Relative Bioavailability Regimen ERegimen 90% PK (after high- D Point Confidence Paramenter fat meal(fasting) Estimate interval C_(max) 76.8 63.7 1.197 1.027-1.395 AUC_(t)564 477 1.184 1.042-1.344 AUC_(inf) 577 491 1.171 1.035-1.306 As can beseen from Tables 14A and 14B, there is no clinically meaningful foodeffect for the 30 mg ER tablets. Administration following a high-fatmeal increased the Compound 1 mean AUC and C_(max) by 17% and 20%,respectively.

Example 25: Observed Steady State Exposures for 15 mg and 30 mg ExtendedRelease Tablets Under Non-Fasting Conditions

The steady state pharmacokinetic profile of the 15 mg once dailyextended release (ER) tablets (prepared in Example 5) and the 30 mg oncedaily ER tablets (prepared in Example 8) was evaluated.

Healthy human subjects (n=24) were assigned to one of two regimens.Subjects in Regimen F (n=12) were administered the 15 mg ER tablet fromExample 5 once daily for seven days under non-fasting conditions.Subjects in Regimen G (n=12) were administered the 30 mg ER tablet fromExample 8 once daily for seven days under non-fasting conditions. Ondays one and seven, serial blood samples were collected from eachsubject prior to the daily dosing and up to 24 hours after dosing. Uponcollection, the samples were promptly placed in an ice bath, and within2 hours after sample collection they were centrifuged at about 4° C. Theresulting plasma samples were placed in clean polypropylene-tubes andstored in a freezer until analysis. The plasma samples were assayed forCompound 1 using appropriate liquid chromatography mass spectrometryprocedures. Pharmacokinetic parameters were estimated usingnon-compartmental methods, and summary statistics were computed for eachparameter by regimen.

The results are summarized in Table 15A.

TABLE 15A Mean (% CV)^(e) Pharmacokinetic Parameters for Compound 1Following Administration of 15 mg ER Tablet or 30 mg ER Tablet QD forSeven Days (Non-Fasting) Regimen F Regimen G (15 mg ER Tablet) (30 mg ERTablet) PK Parameter Units Day 1 Day 7 Day 1 Day 7 C_(max) ng/mL 36.8(26) 36.0 (24) 74.3 (32) 79.5 (40) T_(max) ^(a) hours 4.0 (3.0-6.0) 4.0(2.0-6.0) 40 (2.0-6.0) 4.0 (1.5-6.0) AUC₂₄ ng · h/mL 305 (24) 317 (21)517 (30) 582 (30) C₂₄ ng/mL 2.42 (45) 3.22 (46) 4.27 (48) 5.25 (44)C_(trough) ng/mL — 2.96 (35) — 5.02 (42) C_(min,ss) ng/mL — 2.80 (41) —4.62 (38) Fluctuation Index % 291 (14) 251 (14) 345 (14) 306 (17)t_(1/2) ^(b) hours — 9.43 (76) — 10.4 (44) C_(max) to C₂₄ ratio 17(7.8-44) 13 (5.6-35) 17 (9.9-38) 14 (7.0-30) C_(max)/Dose (ng/mL)/mg2.46 (26) 2.40 (24) 2.48 (32) 2.65 (40) C_(trough)/Dose (ng/mL)/mg 0.16(45) 0.21 (46) 0.14 (48) 0.18 (44) AUC₂₄/Dose (ng · h/mL)/mg 20.3 (24)21.2 (21) 17.2 (30) 19.4 (30) R_(AUC) ^(c) — 1.02 (0.91-1.40) — 1.16(0.92-1.31) R_(Cmax) ^(d) — 1.00 (0.84-1.26) — 1.02 (0.82-1.40)^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-% CV) ^(c)R_(AUC)= AUC₂₄Day 7/AUC₂₄Day 1; median (range) ^(d)R_(Cmax) = C_(max)Day7/C_(max)Day 1; median (range) ^(e)Data in parentheses is thecoefficient of variance of the PK parameter (% CV), unless otherwiseindicated

As can be seen from this data, the observed steady state C_(max) andAUC₂₄ following 15 mg QD and 30 mg QD administration are generallyconsistent with the single dose and food-effect results obtained inExamples 45-47. The bioavailability of the 15 mg and 30 mg ER tablets is70% to 80% relative to the same dose of IR capsules.

Example 26: Observed Steady State Exposures for 15 mg Extended ReleaseTablets and 6 me Immediate Release Capsules Under Fasting Conditions

The steady state pharmacokinetic profile of the 15 mg once dailyextended release (ER) tablets (prepared in Example 5) under fastingconditions was evaluated, and compared to that of a 6 mg immediaterelease (IR) twice daily (BID) capsule comprising Tartrate Hydrate asthe active.

Healthy human subjects were assigned to one of two regimens underfasting conditions in a randomized, two-period, cross-over study design.Subjects in Regimen K (n=12 at onset; n=11 on Day 7) were administeredthe 6 mg IR capsule twice daily for seven days under fasting conditions.Subjects in Regimen L (n=62) were administered the 15 mg ER tablet fromExample 5 once daily for seven days under fasting conditions. On daysone and seven, serial blood samples were collected from each subjectprior to the daily dosing and up to 24 hours after dosing. Blood sampleswere also collected at 48, 72, 96 and 120 hours after initial dosing.Upon collection, the samples were promptly placed in an ice bath, andwithin 2 hours after sample collection they were centrifuged at about 4°C. The resulting plasma samples were placed in clean polypropylene-tubesand stored in a freezer until analysis. The plasma samples were assayedfor Compound 1 using appropriate liquid chromatography mass spectrometryprocedures. Pharmacokinetic parameters were estimated usingnon-compartmental methods, and summary statistics were computed for eachparameter by regimen.

The results are summarized in Table 16A.

TABLE 16A Mean (% CV)^(e) Pharmacokinetic Parameters for Compound 1Following Administratiou of 6 mg BID (IR) Capsules and 15 mg QD (ER)Tablets for Seven Days (Fasting Conditions) Regimen K Regimen L (6 mg IRCapsules (BID)) (15 mg ER Tablet (QD)) PK Parameter Units Day 1 Day 7Day 1 Day 7 C_(max) ng/mL 36.5 (25) 33.9 (26) 31.7 (40) 31.9 (35)T_(max) ^(a) hours  1.0 (1.0-13)  1.0 (0.5-14)  3.0 (1.5-6.0)  2.5(1.5-4.0) AUC₂₄ ng · h/mL  289 (21)  288 (22)  249 (29)  279 (26) C₁₂ng/mL  2.0 (30)  2.8 (24) — — C₂₄ ng/mL  3.2 (36)  3.6 (23)  1.9 (42) 3.1 (37) C_(min) ng/mL —  2.7 (26) —  3.1 (37) Fluctuation Index %  303(13)  259 (13)  299 (22)  246 (21) t_(1/2) ^(b) hours — 14.7 (77) — 10.3(76) C_(max) to C₂₄ ratio^(a) —   12 (7.7-19)  8.8 (7.4-13)   22(5.8-43)   12 (4.2-20) C_(max) to C_(min) ratio^(a) — —   13 (8.3-18) —  12 (4.2-20) AUC₂₄/Dose (ng · h/mL)/mg 24.8 (23) 24.0 (22) 16.6 (29)18.6 (26) R_(AUC) ^(c) — — 1.02 (0.88-1.09) — 1.11 (0.87-1.99) R_(Cmax)^(d) — — 0.97 (0.68-1.17) — 1.01 (0.65-3.01) ^(a)Median(minimum-maximum) ^(b)Harmonic mean (pseudo-% CV) ^(c)R_(AUC) =AUC₂₄Day7/AUC₂₄Day 1; median (range) ^(d)R_(Cmax) = C_(max)Day7/C_(max)Day 1; median (range) ^(e)Data in parentheses is thecoefficient of variance of the PK parameter (% CV), unless otherwiseindicated

The relative bioavailability for the once-daily (ER) tablet formulation(Regimen L) relative to the twice daily (IR) capsule formulation(Regimen K) at steady state was also determined based on analysis of thenatural logarithms of C_(max), AUC₂₄, C_(min), and C₂₄. The results aresummarized in Table 16B below.

TABLE 16B Relative Bioavailability Estimates and 90% ConfidenceIntervals for 15 mg QD Tablets Relative to 6 mg BID Capsules at SteadyState under Fasting Conditions Relative Bioavailability PK Point 90%Confidence Paramenter Estimate Interval C_(max) 0.909 0.736-1.122 AUC₂₄0.939 0.837-1.053 C_(min) 1.090 0.852-1.395

The ratio of steady-state AUC for the 15 mg QD tablets relative to the 6mg BID capsules was approximately 1, with the 90% confidence intervalswithin the equivalence boundaries. The ratio of the steady-state C_(min)was approximately 1 for the 15 mg QD tablet relative to the 6 mg BIDcapsules.

The pre-morning dose trough concentration (C_(trough)) for the 6 mg BIDcapsules and 15 mg QD tablets was determined prior to the morning doseon Days 2-8. At steady state under fasting conditions, the 15 mg QDtablets provided equivalent AUC₂₄ and comparable C_(max) and C_(min)relative to the 6 mg BID capsules. The steady state C_(min), was 10%lower for the 15 mg QD tablet compared to the 6 mg BID capsule.

Example 27: Observed Steady State Exposures for 30 mg Extended ReleaseTablets and 12 mg Immediate Release Capsules Under Fasting Conditions

The steady state pharmacokinetic profile of the 30 mg once dailyextended release (ER) tablets (prepared in Example 8) under fastingconditions was evaluated, and compared to that of a 12 mg immediaterelease (IR) twice daily (BID) capsule comprising Tartrate Hydrate asthe active.

Healthy human subjects were assigned to one of two regimens underfasting conditions in a randomized, two-period, cross-over study design.Subjects in Regimen M (n=11) were administered the 12 mg IR capsuletwice daily for seven days under fasting conditions. Subjects in RegimenN (n=12 at onset; n=11 at Day 7) were administered the 30 mg ER tabletfrom Example 8 once daily for seven days under fasting conditions. Ondays one and seven, serial blood samples were collected from eachsubject prior to the daily dosing and up to 24 hours after dosing. Bloodsamples were also collected at 48, 72, 96 and 120 hours after initialdosing. Upon collection, the samples were promptly placed in an icebath, and within 2 hours after sample collection they were centrifugedat about 4° C. The resulting plasma samples were placed in cleanpolypropylene-tubes and stored in a freezer until analysis. The plasmasamples were assayed for Compound 1 using appropriate liquidchromatography mass spectrometry procedures. Pharmacokinetic parameterswere estimated using non-compartmental methods, and summary statisticswere computed for each parameter by regimen.

The results are summarized in Table 17A. The mean plasma concentrationof Compound 1 at each time point measured for each of the two regimensis set forth in FIG. 22.

TABLE 17A Mean (% CV)^(e) Pharmacokinetic Parameters for Compound 1Following Administration of 12 mg BID (IR) Capsules and 30 mg QD (ER)Tablets for Seven Days (Fasting Conditions) Regimen M Regimen N PK (12mg IR Capsules (BID)) (30 mg ER Tablet (QD)) Parameter Units Day 1 Day 7Day 1 Day 7 C_(max) ng/mL 80.8 (23) 73.9 (19) 65.7 (22) 68.2 (30)T_(max) ^(a) hours  1.0 (0.5-13)  1.0 (0.5-1.5)  2.5 (1.5-4.0)  3.0(2.0-4.0) AUC₂₄ ng · h/mL  497 (15)  534 (18)  454 (23)  525 (23) C₁₂ng/mL  3.0 (46)  4.1 (55) — — C₂₄ ng/mL  6.5 (54)  6.9 (37)  2.8 (37) 4.4 (39) C_(min) ng/mL —  3.8 (58) —  3.8 (43) Fluctuation Index %  388(15)  317 (14)  349 (12)  291 (17) t_(1/2) ^(b) hours —  7.3 (60) 14.4(64) C_(max) to C₂₄ ratio^(a) —   15 (5.4.-20)   12 (5.9-16)   29(13-38)   17 (4.1-33) C_(max) to C_(min) ratio^(a) — —   19 (8.4-31) —  17 (11-37) AUC₂₄/Dose (ng · h/mL)/mg 21.1 (15) 22.3 (18) 15.1 (22)17.5 (23) R_(AUC) ^(c) — — 1.08 (0.97-1.18) — 1.11 (0.79-1.67) R_(Cmax)^(d) — — 0.98 (0.65-1.18) — 1.03 (0.40-1.82) ^(a)Median(minimum-maximum) ^(b)Harmonic mean (pseudo-% CV) ^(c)R_(AUC) =AUC₂₄Day7/AUC₂₄Day 1; median (range) ^(d)R_(Cmax) = C_(max)Day7/C_(max)Day 1; median (range) ^(e)Data in parentheses is thecoefficient of variance of the PK parameter (% CV), unless otherwiseindicatedaMedian (ininimum-maximum)

The relative bioavailability for a single dose of the once-daily (ER)tablet formulation (Regimen N) relative to the twice daily (IR) capsuleformulation (Regimen M) was also determined based on analysis of thenatural logarithms of C_(max), AUC₂₄, C_(min), and C₂₄. The results aresummarized in Table 17B below.

TABLE 17B Relative Bioavailability Estimates and 90% ConfidenceIntervals for 30 mg QD Tablets Relative to 12 mg BID Capsules at SteadyState under Fasting Conditions Relative Bioavailability PK Point 90%Confidence Paramenter Estimate Interval C_(max) 0.900 0.732-1.107 AUC₂₄0.974 0.869-1.092 C_(min) 0.874 0.747-1.022

The ratio of steady-state AUC for the 30 mg QD tablets relative to the12 mg BID capsules was approximately 1, with the 90% confidenceintervals within the equivalence boundaries. The steady-state C_(min)for the 30 mg QD tablet was approximately 13% lower than for the 12 mgBID capsules. Outliers with high C_(min) in the 12 mg BID dose may havecontributed to this difference.

The pre-morning dose trough concentration (C_(trough)) for the 12 mg BIDcapsules and 30 mg QD tablets was determined prior to the morning doseon Days 2-8. The results show that, at steady state under fastingconditions, the 30 mg QD tablets provided equivalent AUC₂₄ andcomparable C_(max) and C_(min) relative to the 12 mg BID capsules. Thesteady state C_(max), was 10% lower for the 30 mg QD tablet compared tothe 12 mg BID capsules.

Example 28: Comparison of AM vs. PM Pharmacokinetic Profile FollowingAdministration of 6 mg or 12 mg Immediate Release Capsules Under FastingConditions

The pharmacokinetic profile of the 6 mg immediate release (IR) twicedaily (BID) capsules and the 12 mg IR twice daily capsules wasdetermined on Day 7 of Regimen K (Example 26) and Regimen M (Example27), respectively, after administration of the morning (AM dose) andevening (PM dose). The results are summarized in Table 18.

TABLE 18 Mean (% CV)^(b) Pharmacokinetic Parameters for Compound 1Following Administration of AM and PM Doses of 6 mg and 12 mg ImmediateRelease Capsules on Day 7 (Fasting Conditions) Regimen K Regimen M (6 mgIR Capsules) (12 mg IR Capsules) PK Parameter Units AM Dose PM Dose^(c)AM Dose PM Dose^(c) C_(max) ng/mL 33.6 (28) 24.4 (22) 73.9 (19) 46.0(26) T_(max) ^(a) hours 1 (0.5-1.5) 2 (1.0-3.0) 1 (0.5-1.5) 3 (1.0-4.0)AUC₁₂ ng · h/mL 152 (26) 153 (19) 290 (19) 244 (19) C₁₂ ng/mL 2.76 (24)3.63 (23) 4.1 (55) 6.94 (37) C_(max)/C₁₂ — 12.3 (23) 6.9 (22) 18.0 (30)7.4 (39) ^(a)Median (Minimum-Maximum) ^(b)Data in parentheses is thecoefficient of variance of the PK parameter (% CV), unless otherwiseindicated ^(c)The PM dose was administered 3 hours after starting dinnerand 4 hours before a snack.

Example 29: Evaluation of the In Vivo Pharmacokinetic Profile of 30 mgExtended Release Tablets

The pharmacokinetic profiles of the 30 mg once-daily extended release(ER) tablets that were prepared in Examples 14 (ER10, 30% tartaricacid), 15 (ER11, 20% tartaric acid), and 16 (ER12, 10% tartaric acid)using wet granulation were evaluated, and compared to that of the 30 mgER tablet that was prepared in Example 8 (ER8, 30% tartaric acid) usingdirect compression (no wet granulation). The effect of a high-fat mealon the Example 14, 15, and 16 formulations was also evaluated.

Healthy human subjects (n=36) were administered a single dose of the 30mg ER (once daily) tablet from Example 8 (ER8). Example 14 (ER10),Example 15 (ER11), and Example 16 (ER12) under fasting conditions orafter a high-fat meal (non-fasting), in an open-label, randomized,four-period, incomplete crossover study. Doses in the four periods wereseparated by at least four days. Dosing regimens were as set forth belowin Table 19A.

TABLE 19A Dosing Regimens Regimen Dose Formulation Fasting/Non-Fasting_A Single 30 mg Example 8 (ER8) Fasting B Single 30 mg Example 14 (ER10)Fasting C Single 30 mg Example 14 (ER10) Non-Fasting D Single 30 mgExample 15 (ER11) Fasting E Single 30 mg Example 15 (ER11) Non-Fasting FSingle 30 mg Example 16 (ER12) Fasting G Single 30 mg Example 16 (ER12)Non-Fasting

Serial blood samples were collected from each subject prior to dosingand for 72 hours after dosing in each study period. Upon collection, thesamples were promptly placed in an ice bath, and within 1 hour aftersample collection they were centrifuged at about V° C. The resultingplasma samples were placed in clean polypropylene-tubes and stored in afreezer until analysis. The plasma samples were assayed for Compound 1using appropriate liquid chromatography mass spectrometry procedures.Pharmacokinetic parameters were estimated using non-compartmentalmethods, and summary statistics were computed for each parameter byregimen.

Bioavailability Under Fasting Conditions

TABLE 19B Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of a Single 30 mg Dose of Various Compound 1Once-Daily Formulations Prepared Using Wet Granulation Compared toAdministration of a Single 30 mg Dose of a Compound 1 Once-DailyFormulation Prepared Via Direct Compression Under Fasting ConditionsRegimen A Regimen B Regimen D Regimen F PK (ER8) (ER10) (ER11) (ER12)Parameter Units (n = 36) (n = 24) (n = 24) (n = 24) C_(max) ng/mL 57.0(33) 55.8 (27) 61.0 (25) 58.6 (34) T_(max) ^(a) hours  2.5 (1.0-4.0) 3.0 (1.0-4.0)  2.0 (1.0-4.0)  2.0 (1.0-4.0) AUC_(t) ng · h/mL  495 (24) 473 (24)  487 (22)  481 (23) AUC_(inf) ng · h/mL  513 (26)  484 (24) 499 (22)  495 (23) t_(1/2) ^(b) hours  9.2 (61) 10.1 (50)  9.0 (61) 9.3 (63) ^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-% CV)^(c)Data in parentheses is coefficient of variance of the PK parameter(% CV), unless otherwise indicated.

The relative bioavailability for a single dose of the three once-daily(ER) tablet formulations prepared using wet granulation (Regimens B, D,and F) relative to the ER tablet prepared via direct compression (no wetgranulation) (Regimen A) was also determined based on analysis of thenatural logarithms of C_(max), AUC_(t), and AUC_(inf). The results aresummarized in Table 19C below.

TABLE 19C Bioavailability for Three Compound 1 Once-Daily FormulationsPrepared Using Wet Granulation (30 mg; ER10, ER11, ER12) Relative to aFormulation Prepared Via Direct Compression (30 mg, ER8) under FastingConditions Relative Bioavailability PK Point 90% Confidence RegimensParamenter Estimate Interval Regimen B (ER10) C_(max) 1.024 0917-1.143vs. AUC_(t) 0.990 0.933-1.049 Regimen A (ER8) AUC_(inf) 0.9760.918-1.037 Regimen D (ER11) C_(max) 1.063 0.952-1.187 vs. AUC_(t) 0.9850.929-1.044 Regimen A (ER8) AUC_(inf) 0.977 0.919-1.038 Regimen F (ER12)C_(max) 1.034 0.926-1.154 vs. AUC_(t) 0.958 0.904-1.016 Regimen A (ER8)AUC_(inf) 0.958 0.901-1.018

As can be seen from this data, all three of the 30 mg tablets preparedusing wet granulation (ER10, ER11, and ER12) were bioequivalent underfasting conditions to the tablet prepared via direct compression (no wetgranulation).

Effect of a High-Fat Meal on Example 37 Formulation (ER10)

The effect of a high-fat meal on the pharmacokinetic parameters of theExample 14 (ER10, 30 mg active, 30% tartaric acid) formulation issummarized in Table 19D.

TABLE 19D Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of Single 30 mg Dose of the Once-Daily TabletFormulation ER10 under Fasting Conditions and After High-Fat MealRegimen B Regimen C PK (ER10, fasting) (ER10, high fat meal) ParameterUnits (n = 24) (n = 12) C_(max) ng/mL 55.8 (27) 76.3 (30) T_(max) ^(a)hours  3.0 (1.0-4.0)  4.0 (1.5-8.0) AUC_(t) ng · h/mL  473 (24)  605(23) AUC_(inf) ng · h/mL  484 (24)  609 (23) t_(1/2) ^(b) hours 10.1(50)  9.1 (35) ^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-%CV) ^(c)Data in parentheses is coefficient of variance of the PKparameter (% CV), unless otherwise indicated.

The relative bioavailability for a single dose of the Example 14formulation (ER10) administered after a high-fat meal relative toadministration under fasting conditions was also determined based onanalysis of the natural logarithms of C_(max), AUC_(t), and AUC_(inf).The results are summarized in Table 19E below.

TABLE 19E Bioavailability of Single Dose of the 30 mg Once-Daily TabletER10 Administered after High-Fat Meal Relative to under FastingConditions Relative Bioavailability PK Point 90% Confidence ParamenterEstimate Interval Regimen C (ER10, high- C_(max) 1.322 1.134-1.541 fatmeal) AUC_(t) 1.296 1.194-1.405 vs. AUC_(inf) 1.278 1.174-1.392 RegimenB (ER10, fasting)

As can be seen from this data, a high-fat meal increased the C_(max) andAUC_(inf) for the ER10 formulation (30 mg active, 30% tartaric acid) byabout 32% and 28%, respectively.

Effect of a High-Fat Meal on Example 38 Formulation (ER11) The effect ofa high-fat meal on the pharmacokinetic parameters of the Example 15(ER11, 30 mg, 20% tartaric acid) formulation is summarized in Table 19F.

TABLE 19F Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of Single 30 mg Dose of the Once-Daily TabletFormulation ER11 under Fasting Conditions and After High-Fat MealRegimen D Regimen E PK (ER11, fasting) (ER11, high fat meal) ParameterUnits (n = 24) (n = 12) C_(max) ng/mL 61.0 (25) 82.2 (33) T_(max) ^(a)hours  2.0 (1.0-4.0)  4.0 (3.0-8.0) AUC_(t) ng · h/mL  487 (22)  648(24) AUC_(inf) ng · h/mL  499 (22)  657 (24) t_(1/2) ^(b) hours  9.0(61)  9.7 (53) ^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-%CV) ^(c)Data in parentheses is coefficient of variance of the PKparameter (% CV), unless otherwise indicated.

The relative bioavailability for a single dose of the Example 15formulation (ER11) administered after a high-fat meal relative toadministration under fasting conditions was also determined based onanalysis of the natural logarithms of C_(max), AUC_(t), and AUC_(inf).The results are summarized in Table 19G below.

TABLE 19G Bioavailability of Single Dose of the 30 mg Once-Daily TabletER11 Administered after High-Fat Meal Relative to under FastingConditions Relative Bioavailability PK Point 90% Confidence ParamenterEstimate Interval Regimen E (ER11, high- C_(max) 1.343 1.153-1.563 fatmeal) AUC_(t) 1.305 1.204-1.415 vs. AUC_(inf) 1.285 1.181-1.398 RegimenD (ER11, fasting)

As can be seen from this data, a high-fat meal increased the C_(max),and AUC_(inf) for the ER11 formulation (30 mg active, 20% tartaric acid)by about 34% and 29%, respectively, which was a similar food effect asthat observed for the Example 14 (ER10) tablet.

Effect of a High-Fat Meal on Example 16 Formulation (ER12)

The effect of a high-fat meal on the pharmacokinetic parameters of theExample 16 (ER12, 30 mg active, 10% tartaric acid) formulation issummarized in Table 19H.

TABLE 19H Mean (% CV)^(c) Pharmacokinetic Parameters for Compound 1Following Administration of Single 30 mg Dose of the Once-Daily TabletFormulation ER12 under Fasting Conditions and After High-Fat MealRegimen E Regimen G PK (ER12, fasting) (ER12, high fat meal) ParameterUnits (n = 24) (n = 12) C_(max) ng/mL 58.6 (34) 84.2 (33) T_(max) ^(a)hours  2.0 (1.0-4.0)  4.0 (4.0-6.0) AUC_(t) ng · h/mL  481 (23)  615(24) AUC_(inf) ng · h/mL  495 (23)  622 (23) t_(1/2) ^(b) hours  9.3(63) 11.7 (91) ^(a)Median (minimum-maximum) ^(b)Harmonic mean (pseudo-%CV) ^(c)Data in parentheses is coefficient of variance of the PKparameter (% CV), unless otherwise indicated.

The relative bioavailability for a single dose of the Example 16formulation (ER12) administered after a high-fat meal relative toadministration under fasting conditions was also determined based onanalysis of the natural logarithms of C_(max), AUC_(t), and AUC_(inf).The results are summarized in Table 19I below.

TABLE 191 Bioavailability of Single Dose of the 30 mg Once-Daily TabletER12 Administered after High-Fat Meal Relative to under FastingConditions Relative Bioavailability PK Point 90% Confidence ParamenterEstimate interval Regimen G (ER12, C_(max) 1.527 1.314-1.774 high-fatmeal) AUC_(t) 1.295 1.196-1.402 vs. AUC_(inf) 1.272 1.171-1.381 RegimenF (ER12, fasting)

As can be seen from this data, a high-fat meal increased the C_(max) andAUC_(inf) for the ER12 formulation (30 mg active, 10% tartaric acid) byabout 53% and 27%, respectively.

Example 30: Predicted Pharmacokinetic Parameters for 15 mg ExtendedRelease Tablets

The mean pharmacokinetic parameters under fasting conditions for theonce daily (QD) 15 mg extended release tablets prepared in Examples 17(ER13), 18 (ER14), and 19 (ER15) using wet granulation were extrapolatedfrom the single dose data obtained in Example 29 for the Examples 14(ER10), 15 (ER11), and 16 (ER12) formulations, respectively, underfasting conditions. The results are set forth in Table 20A.

TABLE 20A Predicted Mean Pharmacokinetic Parameters under FastingConditions for Compound 1 Following Administration of Single 15 mgOnce-Daily Formulations (Extrapolated from Single- Dose Profiles inExample 52 for 30 mg Doses) PK Single 15 mg Single 15 mg Single 15 mgParameters Units Dose (ER 13) dose (ER14) dose (ER15) C_(max) ng/mL 27.930.5 29.3 T_(max) ^(a) h 3.0 2.0 2.0 AUC_(inf) ng · h/mL 242 250 248^(a)Median (minimum-maximum)

Example 31: Preliminary Data from Phase 1 Study in Healthy Volunteersand Patients with Rheumatoid Arthritis

Compound 1 has been studied in 2 Phase 1 studies, first in human singleascending dose study (Study M13-401, described in WO 2015/061665, andreferred to herein as Study 1), and then in a multiple ascending dosestudy (Study M13-845, also generally referred to in WO 2015/061665, andreferred to herein as Study 2).

In Study 1, a total of 42 healthy volunteers received a single dose ofCompound 1. In Study 2, a total of 32 healthy volunteers receivedmultiple doses of Compound 1 for 14 days (Study 2, Part 1). In addition,14 patients with RA were enrolled and completed the double-blind Part 2of Study 2. The study was designed as a multiple-dose, randomized,multicenter trial, with the primary objective as assessing the safety,tolerability, and PK of multiple ascending doses of Compound 1 inhealthy adult volunteers and to assess the safety, tolerability, and PKof multiple doses of Compound 1 in patients with RA who are on a stablemethotrexate regimen.

Details of Study 1 and Study 2 and results obtained therefrom areprovided below.

Study 1—Single-Dose Escalation in Healthy Subjects

Study 1 was a single-dose escalation evaluation of Compound 1. Study 1was designed as a single-site, randomized, double-blind,placebo-controlled study. Fifty-six subjects in general good health wererandomized to receive single doses of Compound 1 immediate releasecapsules comprising Tartrate Hydrate (1, 3, 6, 12, 24, 36, and 48 mg) orplacebo in a 3:1 ratio with 8 subjects in each dose level. Study drugwas administered following at least 10 hours of fasting. The study wasconducted at PPD Development (Austin, Tex.). Subjects were confined tothe study site and supervised for approximately 8 consecutive days.Study protocol and informed consent were approved by RCRC institutionalreview board (IRB) (Austin, Tex.).

Study 2—Multiple-Dose Escalation

In Study 2, multiple twice-daily (BID) doses of immediate releasecapsules comprising Tartrate Hydrate were administered to healthysubjects (Part 1) or to subjects with rheumatoid arthritis (RA)receiving stable doses of methotrexate (Part 2). Both evaluationsfollowed randomized, double-blind, placebo-controlled designs. Part 1was conducted at PPD Development (Austin, Tex.) and Part 2 was conductedat two sites: Aspen Clinical Research (Orem, Utah) and Altoona Centerfor Clinical Research (Duncansville, Pa.). Study protocol and informedconsents were approved by RCRC IRB (Austin, Tex.) and Quorum Review IRB(Seattle, Wash.).

Study 2—Part 1—Multiple-Dose Escalation in Healthy Subjects

The objective of Part 1 of the multiple-dose study was to characterizethe pharmacokinetics, safety, and tolerability of multiple oral doses ofCompound 1 immediate release capsules comprising Tartrate Hydrate inhealthy subjects. Four escalating dosing regimens (3, 6, 12, and 24 mgCompound 1 or matching placebo twice daily for 13 consecutive days andonce in the morning on Day 14) were evaluated. Study drug wasadministered approximately 30 minutes after a standard breakfast (in themorning) or a snack (in the evening). Forty-four healthy subjectsparticipated in this part of the study with 11 subjects per dose group(8:3 Compound 1: placebo ratio). Subjects were confined to the studysite and supervised for approximately 18 days.

Study 2—Part 2—Multiple-Dose Evaluation in Subjects with RA

The objective of Part 2 of the multiple dose study was to assess thepharmacokinetics, safety, and tolerability of multiple oral doses ofCompound 1 immediate release capsules comprising Tartrate Hydrate insubjects with mild to moderate RA who were on stable methotrexatetreatment. This evaluation was designed to enroll approximately 32subjects randomized in a 1:1:1:1 ratio to one of four paralleltwice-daily regimens (6, 12, and 24 mg Compound 1 and placebo). Subjectsreceived study drug for 26 consecutive days (Study Days 3 through 28)and a single morning dose of study drug on Study Day 29. Compound 1 wasadministered following breakfast for the morning dose and dinner orsnack for the evening dose. Subjects were on methotrexate therapy for atleast 3 months and on a stable dose of 10 to 25 mg/week of methotrexatefor at least 4 weeks prior to the first dose of study drug administeredon Study Day 3 and continued their weekly stable dose of methotrexate onStudy Days 1, 8, 15, 22 and 29. Subjects were confined to the study sitefor a total of 10 days—from Day 1 to Day 4 and from Day 27 to Day 31.

Study Participants

Subjects underwent screening procedures within 30 days prior to theinitial administration of study drug. Subjects signed a written informedconsent prior to the initiation of any screening or study-specificprocedures. Subjects were eligible for study participation if they weremen or women between 18 and 55 years of age (Study 1 and Study 2—Part 1)or 18 to 75 years of age (Study 2—Part 2); judged to be in good generalhealth based upon the results of medical history, laboratory profile,physical examination, chest x-ray, and 12-lead electrocardiogram (ECG);and their body mass index (BMI) was within 19 to 29 kg/m² (Study 1 andStudy 2—Part 1) or within 19 to 39 kg/m² (Study 2—Part 2) at screening.Subjects were considered eligible to participate in Study 2—Part 2 ifthey had diagnosis of RA based on the 2010 American College ofRheumatology/European League against Rheumatism criteria≥6 months, havebeen on methotrexate therapy≥3 months (and folate or equivalent for atleast 2 weeks prior to Study Day 1), on a stable methotrexate dose of 10to 25 mg/week for at least 4 weeks prior to the first dose of study drugadministered on Study Day 3.

In both studies, subjects were excluded if they had any clinicallysignificant abnormalities, infection, major febrile illness,hospitalization, or had any clinically relevant surgical procedurewithin 30 days prior to the first dose of study drug; had positive testresult for hepatitis A virus immunoglobulin M, hepatitis B surfaceantigen, or hepatitis C virus antibody, or HIV antibodies at Screening;had history or evidence of active or latent tuberculosis; had history ofdiabetes or lymphoproliferative disease or evidence of immunosuppression(except for use of methotrexate in Study 2—Part 2); or had clinicallysignificant findings at Screening as determined by the principalinvestigator. Additionally, subjects in Study 2—Part 2 were excluded ifthey had a history of acute inflammatory joint disease of differentorigin other than RA or had current or expected need for oral intakeof >10 mg prednisone/day or equivalent corticosteroid therapy.

Pharmacokinetic Sampling

In healthy subjects, serial blood samples were collected over 72 hoursafter single dosing (Study 1) or over 12 hours after the first dose(Study Day 1) and over 72 hours after the last dose (Study Day 14) ofstudy drug (Study 2—Part 1). In subjects with RA, serial blood sampleswere collected over 48 hours on Study Day 1 for methotrexate assay, over12 hours following the first Study drug dose on Study Day 3 for Compound1 assay, over 12 hours following the morning Study drug dose on StudyDay 28 for Compound 1 assay, and over 48 hours following the last Studydrug dose on Study Day 29 for Compound 1 and methotrexate assays.Pre-dose trough samples were collected prior to the morning dose onStudy Days 5, 6, 7, 13, and 14 in Study 2—Part 1 to assess attainment ofsteady state.

Urine for Compound 1 assay was collected over a 12-hour interval afterthe last dose was administered on Study Day 14 in Study 2—Part 1 and onStudy Days 28 and 29 in Study 2—Part 2. Urine for methotrexate assay wascollected for 48 hours on Study Day 1 and Study Day 29.

Plasma and urine concentrations of Compound 1 and methotrexate weredetermined using validated liquid chromatography method with massspectrometric detection methods. The lower limits of quantitation (LLOQ)for Compound 1 and methotrexate in plasma were established at 0.0503ng/mL and 1.00 ng/mL, respectively. The LLOQ for Compound 1 andmethotrexate in urine were established at 1.01 ng/mL and 0.0500 μg/mL,respectively. Samples quantified below the LLOQ were reported as zero.For Compound 1 assays, inter-run variability (measured as % coefficientof variation [% CV]) was ≤9.5% for plasma≤8.4% for urine and the meanabsolute bias was ≤6.7% for plasma and ≤5.9% for urine. For methotrexateassay, inter-run variability (% CV) was ≤3.9% for plasma and ≤5.2% forurine and the mean absolute bias was ≤5.4% in plasma and ≤13.1% inurine.

Pharmacokinetic Analyses

Compound 1 and methotrexate pharmacokinetic parameters were determinedusing non-compartmental analyses with Phoenix software (Version 6.3,Certara, Princeton, N.J. USA). Calculated pharmacokinetic parametersincluded the maximum observed plasma concentration (C_(max)), time toC_(max) (T_(max)), trough plasma concentration (C_(trough)), theapparent terminal phase elimination rate constant (β), the terminalphase elimination half-life (t_(1/2)), the area under the plasmaconcentration-time curve (AUC) [from time 0 to time of the lastmeasurable concentration (AUC_(t)), from time 0 to infinity (AUC_(∞))for single dosing, and over a 12-hour dosing interval (AUC₀₋₁₂, orAUC_(12,ss)) for multiple dosing and the apparent oral clearance (CL/F).Compound 1 functional half-life (t_(1/2)F) following multiple dosing wascalculated as ln(2)/(ln[C_(max)/C_(trough)]/τ) at steady state, where τis the 12-hour dosing interval (Dutta et al., Clin. Drug Investig.,2006, Vol. 26(12), pp. 681-690). The accumulation ratio (R_(ac)) wascalculated as the ratio of Compound 1 AUC₀₋₁₂ on Day 14 to Day 1 (Study2—Part 1) or Day 28 to Day 3 (Study 2—Part 2). The percentage ofCompound 1 dose recovered unchanged in urine (f_(e)%) at steady statewas calculated as the amount of Compound 1 recovered in urine over the 0to 12-hour interval (Au, 0.2), divided by the administered dose andmultiplied by 100. Renal clearance (CLr) was calculated as Au,₀₋₁₂/AUC₀₋₁₂ at steady state. Methotrexate f_(e)% was calculated as theamount of methotrexate recovered in urine over the 0 to 48-hour interval(Au, ₀₋₄₈), divided by the administered dose and multiplied by 100. CLrof methotrexate was calculated as Au, ₀₋₄₈/AUC₀₋₄₈. The effect ofco-administration of methotrexate on Compound 1 exposure was assessedfrom the ratios of Compound 1 AUC₀₋₁₂ and C_(max) on Study Day 29 toStudy Day 28. The effect of Compound 1 on methotrexate exposure wasassessed from the ratios of methotrexate AUC_(∞) and C_(max) on StudyDay 29 to Study Day 1.

Safety and Tolerability Assessment

Safety was evaluated based on assessments of adverse events, vitalsigns, physical examination, laboratory metrics, and 12-leadelectrocardiogram (ECG). All subjects who received at least one dose ofstudy drug were included in the safety analyses. Subjects who wereadministered placebo were pooled into a single group within each studyor study part. Laboratory test values and vital signs measurements thatwere above or below the reference range were identified. Subjects werefollowed-up for a total of 7 days in Study 1, 35 days in Study 2—Part 1,and 57 days in Study 2—Part 2. In healthy subjects, clinical adverseevents were graded as described in the Guidance for Industry ToxicityGrading Scale for Healthy Adult and Adolescent Volunteers Enrolled inPreventive Vaccine Clinical Trials (September 2007). In subjects withRA, the severity of adverse events was rated by the investigator as mild(transient and easily tolerated by the subject), moderate (causessubject discomfort and interrupts the subject's usual activities), orsevere (causes considerable interference with the subject's usualactivities and may be incapacitating or life-threatening). One subjectin Study 2—Part 2 was randomized to the placebo arm, but receivedCompound 1 in error on Study Days 10 to 16. Therefore, this subject wasincluded with the Compound 1 cohort for safety assessments

Statistical Analyses

Dose proportionality for Compound in healthy subjects was tested usingthe natural logarithms of dose-normalized C_(max) and AUC followingsingle dosing (Study 1) or for steady-state dose-normalized C_(max),C_(trough), and AUC following multiple dosing (Study 2—Part 1)assessments. Attainment of steady-state following multiple doses inhealthy volunteers was assessed by testing the logarithmictransformation of Compound 1 morning pre-dose concentrations for StudyDays 5, 6, 7, 13, and 14 by repeated measures analysis. Statisticalanalyses were performed using SAS software (Version 9.3; SAS instituteInc., Cary, N.C., USA).

Results

Demographics and Subject Disposition

A total of 56 healthy subjects were enrolled in and completed thesingle-dose evaluation (Study 1) and 44 healthy subjects were enrolledin and completed the multiple-dose evaluation (Study 2—Part 1).Enrollment in the multiple-dose evaluation in subjects with RA (Study2—Part 2) was discontinued early due to slow recruitment rate and 14subjects with RA were actually enrolled and completed this evaluation.No early withdrawals occurred in any of the three evaluations. A summaryof demographic data is presented in Table 21A.

TABLE 21A Baseline Demographics of Study Participants Study 1 Study 2 -Part 1 Study 2 - Part 2 Compound 1 Placebo Compound 1 Placebo Compound 1Placebo N = 42 N = 14 N = 32 N = 12 N = 11 N = 3 Mean Age, 31.0 ± 9.832.4 ± 8.6  33.3 ± 9.9 30.7 ± 5.0 59.3 ± 8.3  58.7 ± 14.3 years ± SDMean Weight,  74.7 ± 10.1 74.3 ± 8.8  74.1 ± 9.9  78.4 ± 13.6  78.5 ±14.9 62.5 ± 6.9 kg ± SD Mean Height,  171 ± 8.9  171 ± 10.2  172 ± 7.9 177 ± 6.2  171 ± 7.3  165 ± 9.9 cm ± SD Sex, number 35 males 11 males29 males 12 males 6 males 3 females (%) (83.3%), 7 (79%), 3 (91%), 3(100%) (54.5%), 5 (100%) females females females (9%) females (16.7%)(21%) (45.5%) Race, number 30 White 11 White 23 White 9 White 10 White 2White (%) (71%), 10 (79%), 3 (72%), 9 (75%), 2 (91%), 1 (67%), 1 Black(24%), Black (21%) Black (28%) Black (17%), Black (9%) Asian (33%) 1Asian (2%), 1 Asian (8%) 1 Other (2%)

Compound 1 Single- and Multiple-Dose Pharmacokinetics in HealthyVolunteers

Compound 1 plasma concentrations reached peak levels at approximately 1to 2 hours after oral dosing of the immediate release capsuleformulation. Compound 1 plasma concentrations declined bi-exponentiallyafterwards with a terminal elimination t_(1/2) of approximately 6 to 15hours after single dosing (Table 21-B) and of 8 to 16 hours aftermultiple twice-daily dosing (Table 21-C). Compound 1 functionalhalf-life, estimated from C_(max) to C_(trough) ratio at steady-state,was approximately 3 hours. After multiple dosing, there was a small butstatistically significant (p<0.05) difference between Compound 1pre-dose concentrations on Study Day 13 (13% lower) compared with StudyDay 5. There was no statistically significant difference in Compound 1pre-dose concentration on Study Day 13 and Study Day 14, indicating thatsteady-state was achieved by Study Day 13. At steady-state, the medianaccumulation ratios for Compound 1 AUC₀₋₁₂ were approximately 1.0 overthe evaluated dose range (Table 21-C).

In the single dose evaluation, 1 mg dose group was excluded from thestatistical analyses for AUC_(∞) as the majority of samples collected atthe terminal phase were below the limit of quantitation for allsubjects. There was no statistically significant difference indose-normalized C_(max) between the highest (48 mg) and the lowest (1mg) dose of Compound 1, and there was no statistically significant trendfor change in the dose-normalized C_(max) values with dose. There was notrend for change in Compound 1 dose-normalized AUC_(∞) with doses overthe 3 to 36 mg dose range (P>0.05); however, the dose-normalized AUC_(∞)following single 48 mg dose was 40% lower than that following 3 mg dose(p<0.05).

Following multiple dosing in healthy subjects, there was nostatistically significant difference (p>0.05) in Compound 1dose-normalized steady-state C_(max), C_(trough), or AUC for the 24 mgtwice-daily regimen compared to the 3, 6, or 12 mg twice-daily regimens.

Overall, Compound 1 exposures appeared to be dose proportionalparticularly over the single dose range of 3 to 36 mg and the multipledose range of 3 mg to 24 mg BID.

TABLE 21B Pharmacokinetic parameters (mean ± standard deviation) ofCompound 1 after administration of single doses of the immediate releaseformulation to healthy subjects Pharmacokinetic 1 mg 3 mg 6 mg 12 mg 24mg 36 mg 48 mg Parameters Cpd. 1 Cpd. 1 Cpd. 1 Cpd. 1 Cpd. 1 Cpd. 1 Cpd.1 (Units) (N = 6) (N = 6) (N = 6) (N = 6) (N = 6) (N = 6) (N = 6)C_(max) (ng/mL) 7.72 ± 2.36 25.0 ± 6.88 38.9 ± 9.96 82.9 ± 12.1  158 ±18.4  277 ± 44.5   314 ± 81.9 T_(max) (h)^(a) 1.3 (1.0-2.0) 1.0(1.0-1.5) 1.0 (1.0-1.5) 1.3 (0.5-1.5) 1.3 (1.0-1.5) 0.8 (0.5-1.0) 1.0(0.5-1.0) t_(1/2) (h)^(b) — 5.9 ± 2.4 11.0 ± 3.4  12.1 ± 7.4  14.5 ±9.0  6.4 ± 4.0 12.2 ± 3.5 AUC_(t) (ng · h/mL) 29.8 ± 5.78  102 ± 27.5 159 ± 37.5  329 ± 48.9  612 ± 78.6 909 ± 201 1030 ± 174 AUC_(∞) (ng ·h/mL) —  103 ± 27.6  160 ± 37.6  331 ± 49.8  615 ± 78.1 911 ± 202 1040 ±174 CL/F (L/h) — 31.3 ± 10.4 39.1 ± 9.06 37.0 ± 6.32 39.5 ± 4.92 41.1 ±8.35  47.6 ± 8.97 ^(a)Median (range) ^(b)Terminal elimination half-life,presented as harmonic meat ± pseudo-standard deviation

TABLE 21C Steady-State (Day 14) Pharmacokinetic parameters (mean ±standard deviation) of Compound 1 following administration of multipletwice-daily oral doses of the immediate release formulation to healthysubjects PK Parameters 3 mg BID 6 mg BID 12 mg BID 24 mg BID (Units) (N= 8) (N = 8) (N = 8) (N = 8) C_(max) (ng/mL) 18.5 ± 5.41 28.8 ± 3.6757.6 ± 11.0 119 ± 16.9 T_(max) (h) 1.5 (0.5-3.0) 2.0 (1.5-3.0) 2.3(1.5-3.0) 1.8 (1.5-2.0) AUC₀₋₁₂ 78.3 ± 70.3  138 ± 16.7  271 ± 52.7  529± 62.6 (ng · h/mL) C_(trough) (ng/mL) 1.46 ± 0.50 2.29 ± 0.41 4.54 ±1.55 9.50 ± 2.57 t_(1/2) (h)^(a) 15.7 ± 10.6 13.6 ± 8.5  7.6 ± 4.8 8.0 ±4.2 t_(1/2)F (h)^(b) 3.2 ± 0.4 3.3 ± 0.3 3.2 ± 0.5 3.3 ± 0.4 CL/F (L/h)40.7 ± 10.6 43.9 ± 5.4  45.5 ± 8.04 46.1 ± 6.44 CL_(τ) (L/h)  7.5 ± 2.348.1 ± 1.8 9.7 ± 2.3 8.6 ± 2.8 f_(e) (%) 19 ± 5  19 ± 6  21 ± 4  19 ± 6 R_(ac) AUC₀₋₁₂ ^(c) 1.1 (0.9-1.2) 1.0 (0.9-1.2) 1.0 (0.9-1.1) 1.0(0.8-1.3) ^(a)Terminal elimination half-life. ^(b)Functional half-lifecalculated from C_(max) to C_(trough) ratio at steady state.^(c)Accumulation ratio for AUC₀₋₁₂.Harmonic mean±pseudo-standard deviation are presented for t_(1/2) andt_(1/2)F. Median and range (minimum to maximum) are presented forT_(max) and R_(ac) AUC₀₋₁₂. BID: twice-daily.

Compound 1 Multiple-Dose Pharmacokinetics in Subjects with RA

In subjects with RA who were on stable doses of methotrexate, Compound 1plasma concentrations reached peak levels at 1 to 2 hours after dosing(Table 21D). The mean terminal elimination half-life of Compound 1ranged from approximately 10 to 14 hours, and the functional half-lifewas approximately 4 hours. The median accumulation ratio of Compound 1after 26 days of twice-daily dosing ranged from 0.8 to 1.4. The medianratio of Compound 1 C_(max) and AUC₀₋₁₂ when administered withmethotrexate (on Study Day 29) to those when administered withoutmethotrexate (Study Day 28) ranged from 0.9 to 1.2, indicating a lack ofsignificant effect of methotrexate co-administration on Compound 1pharmacokinetics. The ratio of Compound 1 exposure in subjects withrheumatoid arthritis to Compound 1 exposure in healthy subjects rangedfrom 1.1 (24 mg twice-daily dose) to 1.6 (6 mg twice-daily dose) forAUC₀₋₁₂ and from 1.2 (24 mg twice-daily dose) to 1.7 (6 mg twice-dailydose) for C_(max).

TABLE 21D Pharmacokinetic parameters (mean ± standard deviation) ofCompound 1 following administration of multiple twice-daily oral dosesto subjects with mild to moderate rheumatoid arthritis on stable dosesof methotrexate PK Compound 1 Compound 1 Compound 1 Parameters 6 mg BID12 mg BID 24 mg BID (Units) (N = 4) (N = 3) (N = 3) Study Day Day 28 Day29 Day 28 Day 29 Day 28 Day 29 C_(max) (ng/mL) 47.1 ± 7.47 42.4 ± 8.8571.1 ± 14.8 60.8 ± 4.01  129 ± 39.0  154 ± 39.5 T_(max) (h) 1.5(1.0-2.0) 2.0 (1.5-3.0) 2.0 (1.5-2.0) 2.0 (1.5-3.0) 1.5 (1.5-4.0) 1.0(0.5-1.5) AUC₀₋₁₂  231 ± 48.5  215 ± 49.2  334 ± 49.4  338 ± 14.5 637 ±143  665 ± 89.8 (ng · h/mL) C_(trough) (ng/mL) 5.81 ± 3.06 4.63 ± 3.485.41 ± 0.98 6.44 ± 1.09 15.3 ± 1.86 14.9 ± 4.37 t_(1/2) (h)^(a) — 9.5 ±3.6 — 14.4 ± 5.3  — 11.5 ± 7.6  t_(1/2)F (h)^(b) — 3.5 ± 0.9 — 3.7 ± 0.2— 3.6 ± 0.1 CL/F (L/h) 26.7 ± 4.96 29.0 ± 5.92 36.4 ± 5.44 35.6 ± 1.5639.1 ± 9.79 36.5 ± 4.70 CL_(r) (L/h) 6.94 ± 4.04 4.93 ± 2.41 6.27 ± 2.794.96 ± 3.34 6.31 ± 0.96 8.60 ± 1.30 f_(e) (%) 25 ± 14 16 ± 5  17 ± 8  14± 10 17 ± 5  24 ± 2  R_(ac) AUC₀₋₁₂ ^(d) 1.4 (1.0-1.8) — 1.2 (0.9-1.4) —1.3 (1.2-1.4) — Day 29/Day 28 0.9 (0.9-1.0) 1.0 (0.9-1.1) 1.0 (0.9-1.2)AUC₀₋₁₂ Ratio^(c) ^(a)Terminal elimination half-life. ^(b)Functionalhalf-life calculated from Cmax to Ctrough ratio at steady state.^(c)Accumulation ratio for AUC₀₋₁₂. Harmonic mean ± pseudo-standarddeviation are presented for t_(1/2) and t_(1/2)F. Median and range(minimum to maximum) are presented for T_(max), accumulation ratios, andDay 29/Day 28 ratios. BID: twice-daily

Effect of Compound 1 Co-Administration on Methotrexate Exposure

Pharmacokinetic parameters of methotrexate when administered before(Study Day 1) and after administration of multiple doses of Compound 1(Day 29) are summarized in Table 21E. Since methotrexate wasadministered weekly and has a short plasma half-life, no plasmaaccumulation was expected with repeated dosing and AUC_(∞) wascalculated for both Days 1 and 29. The median ratio for methotrexateAUC_(∞) and C_(max) when administered after multiple doses of Compound 1(on Study Day 29) to that when administered without Compound 1 (on StudyDay 1) ranged from 0.9 to 1.1 and from 0.8 to 1.2, respectively. Therewas no observed change in methotrexate dose-normalized AUC_(∞) whenadministered with or without Compound 1.

TABLE 21E Pharmacokinetic parameters (mean ± standard deviation) ofmethotrexate following administration to subjects with RA alone (Day 1)or concomitant with Compound 1 (Day 29) Compound 1 Compound 1 Compound 16 mg BID Group 12 mg BID Group 24 mg BID Group Placebo (N = 4) (N = 3)(N = 3) (N = 4) PK Methotrexate Dose (mg) Parameters 16.3 ± 6.6 14.2 ±5.2 14.2 ± 1.4 17.5 ± 5.0 (Units) Day 1 Day 29 Day 1 Day 29 Day 1 Day 29Day 1 Day 29 C_(max)  245 ± 63.6  228 ± 23.0  278 ± 44.0  255 ± 99.9 196 ± 58.6  256 ± 29.3 318 ± 138 354 ± 182 (ng/mL) T_(max) (h) 2.5(1.5-6.0) 1.8 (1.0-2.0) 3.0 (2.0-3.0) 2.5 (2.5-3.0) 3.0 (0-3.0) 2.5(2.0-3.0) 1.8 (1.5-3.0) 1.8 (1.0-4.0) AUC_(∞) 1470 ± 494  1490 ± 424 1670 ± 393  1780 ± 791  966 ± 365 1370 ± 324  1640 ± 470  1590 ± 458 (ng · h/mL) t_(1/2) (h)^(a) 4.0 ± 2.6 4.7 ± 1.3 4.0 ± 0.3 4.2 ± 0.6 3.0± 1.1 3.1 ± 1.3 3.9 ± 0.5 3.8 ± 0.3 CL/F (L/h) 11.8 ± 6.43 10.9 ± 3.438.36 ± 1.28 8.14 ± 1.03 16.9 ± 8.89 10.6 ± 1.61 11.2 ± 3.81 11.3 ± 2.66CL_(r) (L/h) 6.63 ± 3.79 5.43 ± 2.02 6.13 ± 1.93 4.78 ± 2.28 7.46 ± 0.706.43 ± 0.75 4.32 ± 1.12 5.80 ± 1.08 f_(e) (%) 58 ± 29 51 ± 20 74 ± 19 59± 26 54 ± 25 63 ± 4  45 ± 25 57 ± 26 AUC_(∞) Ratio^(b) — 1.0 (0.8-1.4) —0.9 (0.9-1.3) — 1.1 (1.0-3.1) — 0.9 (0.8-1.2) ^(a)Terminal eliminationhalf-life presented as harmonic mean ± pseudo-standard deviation.^(b)Ratio of methotrexate exposure (AUC_(∞)) on Study Day 29 to that onStudy Day 1; median and range (minimum to maximum) are presented.

Safety and Tolerability

Across all three evaluations, a total of 74 healthy subjects and 11subjects with RA received Compound 1 and a total of 26 healthy subjectsand 3 subjects with RA received placebo. There were no dose-limitingtoxicities or safety concerns with Compound 1 from the single doses upto 48 mg or multiple doses up to 24 mg twice daily. Notably, the safetyand tolerability profile of Compound 1 was comparable between subjectswho received Compound 1 or placebo, and between healthy subjects andsubjects with RA on background treatment of methotrexate, though thenumber of subjects with RA was limited. There was no evidence of a doseor time dependency for the incidence of adverse events in either healthysubjects or subjects with RA. There were no study discontinuations dueto adverse events, no serious adverse events and no clinicallysignificant changes in ECG parameters, or laboratory metrics in any ofthe subjects or treatment groups. The maximum tolerated dose of Compound1 was not reached in the single or multiple dose studies. Adverse eventsthat were reported by at least two subjects in Compound 1 or placebogroups in Study 1 or Study 2—Part 1 are presented in Table 21F.

TABLE 21F Treatment-emergent adverse events reported by two or morehealthy subjects administered Compound 1 or placebo in the single andmultiple ascending dose evaluations Single doses (Study 1) 1 mg 3 mg 6mg 12 mg 24 mg 36 mg 48 ng Total Com- Com- Com- Com- Com- Com- Com- Com-System Organ Class Placebo pound 1 pound 1 pound 1 pound 1 pound 1 pound1 pound 1 pound 1 MedDRA Preferred Term (N = 14) (N = 6) (N = 6) (N = 6)(N = 6) (N = 6) (N = 6) (N = 6) (N = 42) Any Adverse Event 3 (21.4%) 0 01 (16.7%) 0 1 (16.7%) 2 (33.3%) 2 (33.3%)  6 (14.3%) Nervous SystemDisorders 0 Headache 0 0 0 0 0 0 0 2 (33.3%) 2 (4.8%) Presyncope* 0 0 01 (16.7%) 0 1 (16.7%) 0 0 2 (4.8%) Multiple twice-daily doses (Study 2 -Part 1) 3 mg 6 mg 12 mg 24 mg Total Com- Com- Com- Com- Com- SystemOrgan Class Placebo pound 1 pound 1 pound 1 pound 1 pound 1 MedDRAPreferred Term (N = 12) (N = 8) (N = 8) (N = 8) (N = 8) (n = 32) AnyAdverse Event 7 (58.3%) 2 (25.0%) 2 (25.0%) 3 (37.5%) 4 (50.0%) 11(34.4%) Gastrointestinal Disorders Abdominal Discomfort 3 (25.0%) 0 0 00 0 Abdominal Pain 0 0 1 (12.5%) 0 1 (12.5%) 2 (6.3%) Diarrhoea 1(8.3%)  0 1 (12.5%) 1 (12.5%) 0 2 (6.3%) Infections and InfestationsNasopharyngitis 2 (16.7%) 1 (12.5%) 1 (12.5%) 0 0 2 (6.3%) NervousSystem Disorders Headache 2 (16.7%) 0 2 (25.0%) 2 (25.0%) 1 (12.5%)  5(15.6%) *The two cases of presyncope were associated with venipuncture.

In healthy subjects who were administered single doses of eitherCompound 1 (1, 3, 6, 12, 24, 36, and 48 mg) or placebo in Study 1, 14.3%(6/42) and 21.4% (3/14) of subjects, respectively, reported to have oneor more treatment-emergent adverse events (TEAEs). All TEAEs wereassessed as mild in severity. The adverse events reported by more thanone subject who received Compound 1 were headache and presyncope (1subject in 6 mg and 1 subject in 24 mg dose group) in association withvenipuncture (see Table 21F).

In healthy subjects who were administered multiple doses of Compound 1(3, 6, 12, and 24 mg BID) or placebo for 14 consecutive days in Study2—Part 1, 34% (11/32) and 58% (7/12) of subjects, respectively, reportedone or more TEAEs. The overall incidences of TEAEs were numericallyhigher at higher doses of Compound 1; 2 (25.0/0), 2 (25.0%), 3 (37.5%)and 4 (50%) subjects in the 3 mg, 6 mg, 12 mg and 24 mg dose groups,respectively; however, these rates were lower than that was observed inthe placebo group (58%). All TEAEs were reported as mild in severity.Four events occurred in at least two subjects who received Compound 1:headache, abdominal pain, diarrhea, and nasopharyngitis; three of theseevents also occurred in subjects who received placebo: headache,diarrhea and nasopharyngitis (Table 21F).

There were no clinically significant changes in any hematologicparameters after multiple-dose administration in healthy subjects for 14days. With increasing doses of Compound 1, there were statisticallysignificant downward trends in mean levels of hemoglobin, RBCs, WBCs andneutrophils; however, even at the 24 mg dose, the mean levels werewithin the normal reference range. The mean changes in reticulocytecounts with increasing dose of Compound 1 compared to placebo were notstatistically significant, suggesting no evidence of a dose relatedeffect on reticulocyte counts after 14 days of Compound 1 treatment.Total cholesterol, HDL-cholesterol, and LDL-cholesterol showed astatistically significant upward trend with increasing Compound 1 dosecompared with placebo; however, the final mean values for these lipidparameters in the Compound 1 dose groups remained within the normalreference range.

Subjects with mild to moderate RA on stable background doses ofmethotrexate, in Study 2—Part 2, were administered multiple doses ofCompound 1 (a total of 11 subjects) or placebo (a total of 3 subjects).Five subjects in the Compound 1 dose groups and two subjects in theplacebo group experienced at least one TEAE. In the Compound 1 dosegroups, 7 TEAEs were reported; nausea, vomiting, viral gastroenteritis,upper respiratory tract infection, post-traumatic neck syndrome, backpain, and insomnia. All TEAEs were reported by the investigators as mildor moderate in severity, and no adverse event was reported in more thanone subject in any treatment group. There was no evidence of a doserelationship with any of these events. Notably, as these subjects withRA received a stable background dose of methotrexate, there were nochanges in hepatobiliary metrics for those receiving Compound 1. Therewas also no evidence of a Compound 1 dose-related effect on renalfunction in these subjects with RA, as evaluated by serum creatinine andblood urea nitrogen values.

Discussion

Compound 1 was well-tolerated after single doses up to 48 mg andmultiple twice daily doses up to 24 mg of Compound 1 immediate-releaseformulation. All adverse events occurred after single- or multiple-doseadministrations were mild to moderate in nature with comparablefrequency between subjects who received Compound 1 or placebo. Noanemia, serious infections, or clinically significant changes inhematology, hepatobiliary or renal laboratory metrics was observed with14 days of repeated Compound 1 dosing in healthy volunteers or 27 daysof dosing in RA patients.

Compound 1 displayed multi-exponential plasma disposition with afunctional half-life of 3 to 4 hours across the dose range of 3 to 24 mgtwice daily of the immediate-release formulation in healthy volunteersand subjects with RA. The terminal elimination half-life of Compound 1ranged from 6 to 16 hours across the different dose levels. However,given the multi-exponential disposition of Compound 1, the longerterminal half-life is less relevant clinically than the functionalhalf-life (Dutta et al., Clin. Drug Investig., 2006, Vol. 26(12). pp.681-690; Sabin, Pharm. Res., 2008, Vol. 25(12), pp. 2869-77). Consistentwith a shorter functional half-life, there was no accumulation acrossthe evaluated 3 to 24 mg twice-daily dose range. While there are nosolid clinical data to suggest that extended exposure is needed forefficacy of JAK inhibitor (i.e. to determine whether efficacy isconcentration driven or AUC driven), the pharmacokinetic profile of theimmediate-release formulation of Compound 1 appears to be generally moresuited for twice-daily dosing than for once-daily dosing.

Compound 1 displayed dose-proportional pharmacokinetics particularlyover the 3 to 36 mg dose range, which encompasses the dose rangesevaluated in Phase 2b clinical trials in RA (3 to 18 mg BID and 24 mgQD), or that is currently being evaluated in Crohn's disease (3 to 24 mgBID).

It has been reported previously that the JAK inhibitors tofacitinib andfilgotinib have higher exposures in subjects with RA than those inhealthy volunteers (see FDA, “Clinical Pharmacology and BiopharmaceuticsReview(s)—Tofacitinib”. Application Number 203214Orig1s000, Center forDrug Evaluation and Research, 2011; Namour et al., Clin. Pharmacokinet.,2015, Vol. 54, pp. 859-874). Compound 1's apparent oral clearance was23% lower in subjects with RA (leading to approximately 30% higherexposure), on average across all dose groups, compared to healthysubjects. In general, older subjects are expected to have lower renaland metabolic capacity compared to younger subjects (Mangoni, Br. JClin. Pharmacol., 2004, Vol. 57(1), pp. 6-14). RA subjects who receivedmultiple-doses of Compound 1 were 26 years older, on average, than thehealthy subjects evaluated in Study 2 (Table 21A); therefore, age cannotbe excluded as potential contributor to the apparently 30% higherexposure of Compound 1 in RA subjects than in healthy subjects.

Methotrexate remains the first line therapy for treatment of RA and isoften used with biologic DMARDs or in combination with other csDMARDs(see Ma, et al., Rheumatology (Oxford), 2010, Vol. 49(1), pp. 91-8;Singh, et al., Arthritis Care Res. (Hoboken), 2012, Vol. 64(5). pp.625-39; Smolen, et al., Ann. Rheum. Dis., 2014, Vol. 73(3), pp.492-509). Therefore, at least in a subset of the RA patients, it isexpected that Compound 1 will be added to the first line therapy,methotrexate; thus, it was important to confirm a lack of any potentialinteraction between Compound 1 and methotrexate. The ratios of Compound1 AUC and C_(max) values when administered with methotrexate to thosewhen administered alone indicate lack of significant effect ofmethotrexate on Compound 1 (Table 21D). Similarly, Compound 1 did nothave any significant effect on methotrexate exposures (Table 21E). Thiswas consistent with the observed safety and tolerability profiles inthese two populations.

In summary. Compound 1 displayed favorable safety and tolerabilityprofiles over single doses up to 48 mg and multiple doses up to 24 mgtwice daily for 14 days in healthy subjects and for 27 days in subjectswith RA. Compound 1 demonstrated a pharmacokinetic profile suitable fortwice-daily dosing with the immediate release formulation. There was nopharmacokinetic interaction between methotrexate and Compound 1 andthere was no accumulation of Compound 1 with repeated administration.

Example 32: Treatment of Moderately to Severely Active RheumatoidArthritis in Patients Who have Inadequately Responded to or areIntolerant to Anti-TNF Therapy

The following example briefly describes the results of a Phase 2b,12-week, randomized, double-blind, parallel-group, placebo-controlledstudy in which adult subjects with moderately to severely activerheumatoid arthritis (RA) who have inadequately responded to or who areintolerant to an anti-tumor necrosis factor (TNF) therapy were treatedwith Compound 1.

The study was conducted in accordance with the International Conferenceon Harmonisation guidelines, applicable regulations, and the principlesof the Declaration of Helsinki. The study protocol was approved by anindependent ethics committee or institutional review board. All patientsprovided written informed consent before participating in anystudy-related procedures.

Participants

Adult men and women aged 18 years or older, who had been diagnosed withRA and fulfilled either the 1987 revised American College ofRheumatology (ACR) classification criteria (Arnett et al, ArthritisRheum., 1988, Vol. 31(3), pp. 315-324) or the 2010 ACR/European LeagueAgainst Rheumatism (EULAR) criteria (Smolen et al, Ann. Rheum. Dis.,2010, Vol. 69(6), pp. 964-975) were enrolled in the study. Active RA wasdefined as subjects having ≥6 swollen joints (based on a 66-jointcount); ≥6 tender joints (based on a 68-joint count); andhigh-sensitivity C-reactive protein (hsCRP)>upper limit of normal (ULN=5mg/L) or seropositivity for both rheumatoid factor (RF) and anti-cycliccitrullinated peptide (CCP). Eligible subjects must have been treatedwith ≥1 anti-TNF biologic agent for ≥3 months but continued toexperience active RA, or discontinued anti-TNF biologic therapy becauseof intolerance or toxicity. In addition, subjects with prior exposure tonon-anti-TNF biologic therapy were allowed to enroll, as long as theyhad failed ≥1 anti-TNF biologic. All biologic therapies had to be washedout prior to randomization: ≥4 weeks for etanercept, ≥8 weeks foradalimumab, infliximab, certolizumab, and golimumab, ≥8 weeks forabatacept, ≥12 weeks for tocilizumab, and >1 year for rituximab. Astable dose of methotrexate (7.5-25 mg/week) was required throughout thestudy. Key exclusion criteria were prior exposure to a JAK inhibitor, ora need for any immunosuppressant other than methotrexate. Subjects withserum aspartate transaminase (AST) or alanine transaminase (ALT)>1.5×ULNor absolute neutrophil count (ANC)<1,200/μL or absolute lymphocytescount<750/μL at screening were excluded.

Study Design and Treatment

The study was a phase 2b, 12-week, randomized, double-blind,parallel-group, placebo-controlled study conducted at 123 sites,enrolling patients in the United States (176 patients, 64%) and PuertoRico (11 patients, 4%); Australia and New Zealand (6 patients, 2%);Western Europe including Belgium, Spain and Great Britain (29 patients,11%); Eastern Europe including Czech Republic. Hungary, Poland (54patients, 20%).

Subjects were equally randomized to receive oral immediate-release dosesof Compound 1 (immediate release capsules comprising Tartrate Hydrate)at 3 mg BID, 6 mg BID, 12 mg BID or 18 mg BID, or matching placebo BID,for 12 weeks. Randomization was performed centrally, according to ablocked randomization schedule, by investigators enrolling via aninteractive voice response system. Subjects, caregivers, investigators,joint assessors, and the study team were blinded to the treatmentadministered. Placebo and Compound 1 capsules were identical inappearance. Subjects should have been taking an oral supplement of folicacid (or equivalent) from four weeks prior to baseline and throughoutthe study. Subjects were allowed to continue stable doses ofmethotrexate and non-steroidal anti-inflammatory drugs (NSAIDS),acetaminophen, or oral corticosteroids (equivalent to prednisone≤10 mg).

Assessments

The primary efficacy endpoint was the proportion of subjects achievingan ACR20 response at Week 12. Secondary endpoints included theproportions of subjects achieving an ACR50/ACR70 response and theproportion of subjects achieving 28-joint count disease activity scorebased on C-reactive protein (DAS28(CRP))≤3.2, or <2.6, at Week 12. Amongthe other endpoints were the proportion of subjects achieving lowdisease activity (LDA) or clinical remission (CR) based on ClinicalDisease Activity Index (CDAI) criteria (LDA, CDAI≤10; CR≤52.8); changein DAS28(CRP), and change in the Health AssessmentQuestionnaire-Disability Index (HAQ-DT) (Anderson et al, Arthritis CareRes. (Hoboken), 2012. Vol. 64(5), pp. 640-647), including the proportionof subjects achieving minimal clinically important difference (MCID) of−0.22 (Strand et al, Rheumatology (Oxford), 2006, Vol. 45(12). pp.1505-1513). A post hoc analysis was performed to determine theproportion of subjects who had a sustained ACR20 response, defined asachievement of the ACR20 criteria at every visit (at Weeks 2, 4, 6, 8and 12).

Safety was evaluated at each scheduled visit during treatment and for 30days after the last dose of study drug on the basis of AEs, serious AEs,vital signs, and laboratory tests (hematology, blood chemistry, andurinalysis). Adverse events were coded according to the MedicalDictionary for Regulatory Activities (MedDRA, version 17.1).Descriptions of AE severity and post-baseline laboratory changes werebased on the Rheumatology Common Toxicity Criteria v.2.0, developed bythe OMERACT Drug Safety Working Group (Woodworth et al., 2007, J.Rheumatol., Vol. 34(6), ppl. 1401-14).

Statistical Methods

All efficacy analyses were conducted in modified intent-to-treatpopulation, which consisted of all randomized patients who received ≥1dose of study drug. For ACR response rates, the last observation carriedforward (LOCF) was the primary missing data imputation method andnon-responder imputation (NRI) was also used to assess the robustness ofthe results. For continuous endpoints including DAS28 (CRP). LOCFmissing data imputation was implemented; NRI is reported for binaryendpoints. Binary endpoints including ACR response rates were analyzedusing chi-square test with normal approximation when comparing eachCompound 1 treatment group to placebo group. Continuous endpoints wereanalyzed using an Analysis of Covariance (ANCOVA) model with treatmentgroup as a factor and baseline measurement as the covariate. TheMultiple Comparison Procedure and Modeling (MCPMod) method wasimplemented to detect any non-flat dose-response relationship byevaluating several non-linear dose-response models at the same time.P-values were not corrected for multiple comparisons.

Assuming ACR20 response rates of 25% in the placebo group and 55% in anyCompound 1 group, a sample size of 50 subjects per group (250 patientstotal) was estimated to provide at least 80% power to detect a 30%difference in response rates between the placebo group and a Compound 1group when using a 1-sided test with an alpha level of 0.05.

Results Subject Disposition and Baseline Characteristics

In total, 276 subjects were randomized; all received their intendedtreatment. The overall study completion rate was 88% (FIG. 4). Baselinesubject characteristics and disease activity were generally similaramong treatment groups (see Table 22A). The mean duration since RAdiagnosis was 12 years. Seventy-two percent of subjects had priorexposure to only one anti-TNF, 28% to ≥2 anti-TNFs, and 20% of subjectswere also exposed to non-anti-TNF biologics. At baseline, subjects hadmean swollen and tender joint counts of 18 (out of 66 joints) and 28(out of 68 joints), 60% subjects had an elevated hsCRP and meanDAS28(CRP) was 5.8.

TABLE 22A Baseline Patient Characteristics and Disease Activity Compound1 Placebo 3 mg BID 6 mg BID 12 mg BID 18 mg BID Characteristic (n = 56)(n = 55) (n = 55) (n = 55) (n = 55) Female, number (%)   48 (86)   43(78)   43 (78)   44 (80)   42 (76) Age, years, mean (SD)   58 (12)   57(13)   56 (12)   59 (11)   57 (12) Duration since RA diagnosis, 12.1(9.0) 11.8 (9.4) 12.3 (10.6) 12.2 (10.2) 10.9 (7.7) years, mean (SD) RFpositive, number (%)   49 (88)   43 (78)   45 (82)   45 (82)   48 (87)Anti-CCP positive, number (%)   48 (86)   45 (82)   45 (82)   45 (82)  47 (86) Used ≥1 prior anti-TNF agent,   42 (76)   39 (71)   38 (70)  38 (72)   38 (69) number (%) Used ≥2 prior anti-TNF   13 (24)   16(29)   16 (30)   15 (28)   17 (31) agents, number (%) Used priornon-anti-TNF   9 (16)   10 (18)   14 (26)   14 (26)   7 (13) agents,number (%)* Disease activity TJC68, mean (SD)   28 (15)   28 (15)   30(16)   26 (16)   26 (15) SJC66, mean (SD)   19 (12)   17 (10)   17 (10)  17 (10)   18 (10) HAQ-DI, mean (SD)  1.6 (0.7)  1.5 (0.7)  1.6 (0.7) 1.6 (0.6)  1.5 (0.6) DAS28 (CRP), mean (SD)  5.8 (0.9)  5.7 (0.9)  5.9(0.9)  5.7 (0.9)  5.8 (1.0) CDAI, mean (SD)   41 (12)   40 (13)   42(12)   40 (12)   41 (14) hsCRP, mg/L, mean (SD)^(‡) 10.1 (13.2) 11.4(11.8) 18.6 (27.4) 14.4 (23.0) 14.0 (15.1) hsCRP >ULN,^(†) n (%)^(‡)  28 (50)   35 (64)   34 (62)   33 (60)   35 (64) Abbreviations:BID-twice daily; CDAI-Clinical Disease Activity Index; DAS28(CRP)-Disease Activity Score-28 joints using C-reactive protein;HAQ-DI-Health Assessment Questionnaire-Disability index;hsCRP-high-sensitivity C-reactive protein; RA-rheumatoid arthritis;SJC66-swollen joint count using 66 joints; TJC68-tender joint countusing 68 joints; TNF-tumor necrosis factor; ULN-upper limit of normal.*Non-TNF biologic agents. ^(†)ULN = 5 mg/L ^(‡)Subjects with normalhsCRP could be enrolled as long as they were positive for rheumatoidfactor and anti-cyclic citrullinated peptide. Modified intent-to-treatpopulation. Percentages were calculated using non-missing values

Efficacy

The primary analysis based on LOCF revealed that an ACR20 response wasachieved by 55.6% (P=0.033), 63.5% (P=0.004), 72.7% (P<0.001), and 70.9%(P<0.001) in subjects treated with Compound 1 at 3, 6, 12, and 18 mgBID, respectively, compared with 35.2% in subjects who received placebo.Analysis based on NRI also demonstrated a statistically significantimprovement in ACR20 response rate in subjects who received any dose ofCompound 1 compared with those who received placebo (FIG. 1A). Asignificant dose-response relationship was observed for all doses ofCompound 1 (P<0.01). The ACR20 response rates (NRI) at Week 12 weresimilar among patients who had received 1 versus ≥2 prior anti-TNFs(FIG. 36B). ACR50 and ACR70 response rates were significantly higher atCompound 1 doses of ≥6 mg BID versus placebo (FIG. 1A).

Significant differences in ACR20 response rates (NRI) were observed atthe first post-baseline assessment (Week 2) in subjects treated withCompound 1 12 mg BID and 18 mg BID versus placebo (P≤0.007; FIG. 2A);the maximum response rate (71%) was observed with the 12 mg BID dose byWeek 8 and plateaued thereafter. Starting at Week 4, there weresignificantly greater ACR50 response rates with Compound 1 doses≥6 mgBID versus placebo; the maximum response rate (42%) was observed withthe 18 mg BID dose by week 8 and plateaued thereafter (FIG. 2B).Improvements in ACR70 response rates better than placebo were observedstarting at Week 6, with peak response of up to 25% at Week 12 (FIG.2C). A sustained ACR20 response (at every visit between Week 2 through12, NRI) was achieved by 13%, 22%, 40% and 27% of subjects in theCompound 1 3 mg, 6 mg, 12 mg and 18 mg BID groups respectively, versus4% in the placebo group. Significant improvements in DAS28(CRP) (LOCF)occurred at the Week 2 assessment with Compound 1 at ≥6 mg BID versusplacebo (P<0.001; FIG. 2D).

A higher percentage of subjects receiving Compound 1 (any dose) achievedDAS28(CRP)≤3.2 or ≤2.6, versus placebo at Week 12 (NRI, FIGS. 2E and 2F)with the difference being statistically significantly for the Compound 112 mg BID group (DAS28(CRP)≤3.2, 49%; DAS28(CRP)<2.6, 33%, P<0.01)compared with placebo (25% and 13%, respectively). Similarly, a higherpercentage of patients treated with any dose of Compound 1 achieved CDAILDA or CR criteria versus placebo at Week 12 (NRI, FIG. 2F). At Week 12,treatment with Compound 1 at 12 mg BID also resulted in statisticallysignificant mean changes from baseline in individual components of theACR score compared with placebo (Table 22B). In addition, asignificantly greater proportion of patients achieved the MCID forHAQ-DI with Compound 1 ≥6 mg BID (58%-64%) as compared with placebo(44%).

TABLE 22B Mean Changes From Baseline in ACR Components at Week 12Compound 1 Placebo 3 mg BID 6 mg BID 12 mg BID 18 mg BID ACR Component(n = 55) (n = 54) (n = 53) (n = 55) (n = 55) TJC68 −9.3 −13.4 −15.7**−16.8** −15.1* (−12.5, −6.1) (46.6, −10.1) (−19.0, −12.5) (−20.1, −13.6)(−18.3, −11.9) S5C66 −6.4 −9.5 −9.2 −10.0* −9.2 (−8.7, −4.2) (−11.8,−7.2) (−11.4, −6.9) (−12.3, −7.8) (−11.5, −7.0) Patient's −16.5 −24.7−31.4**,^(†) −36.3*** −35.0*** assessment of pain (−23.5, −9.5) (−31.8,−17.6) (−38.6, −24.2) (−43.3, −29.3) (−42.0, −27.9) PhGA −29.6^(‡) −33.8−37.5 −43.5*** −42.4** (−35.3, −23.8) (−39.4, −28.1) (−43.2, −31.7)(−49.1, −37.9) (−48.0, −36.8) PtGA −20.0 −24.2 −29.9^(†) −37.4***−33.5**,^(†) (−27.0, −13.0) (−31.3, −17.1) (−37.1, −22.6) (−44.4, −30.4)(−40.6, −26.5) HAQ-DI −0.2 −0.3 −0.5**,^(†) −0.5* −0.5**,^(†) (−0.4,−0.1) (−0.4, −0.1) (−0.6, −0.3) (−0.6, −0.3) (−0.7, −0.4) HAQ-DI≤MCID,^(§) 24 (44), 27 (50), 30 (58), 35 (64), 34 (63), n (%), 95% CI31-57 37-63 44-71^(†) 51-76 50-76^(†) hsCRP, mg/L −0.4 −7.9* −9.7**−6.8* −6.9* (−4.6, 3.9) (−12.2, −3.6) (−14.1, −5.4) (−11.1, −2.6)(−11.1, −2.6) Data are mean (95% CI), unless otherwise noted.Abbreviations: ACR-American College of Rheumatology; BID-twice daily;HAQ-DI-Health Assessment Questionnaire-Disability index;hsCRP-high-sensitivity C-reactive protein; LOCF-last observation carriedforward; MCID-minimal clinically important difference; PhGA-physician'sglobal assessment of disease activity; PtGA-patient global assessment ofdisease activity; RA-rheumatoid arthritis; SJC66-swollen joint countusing 66 joints; TJC68-tender joint count using 68 joints. *P < 0.05;**P < 0.01; ***P < 0.001 relative to placebo. ^(†)1 patient with missingdata. ^(‡)2 patients with missing data. ^(§)MCID = −0.22. Modifiedintent-to-treat population (LOCF).

Safety

The percentage of subjects with any treatment-emergent AEs wasnumerically higher in a dose-dependent manner for the Compound 1 6, 12and 18 mg BID treatment groups compared with placebo (Table 22C). Mostreported AEs were considered mild to moderate in severity. The mostcommonly observed AEs were headache, nausea, upper respiratory tractinfection, and urinary tract infection. The incidences of serious AEsand severe AEs were low, without an apparent dose-response relationship(Table 22C). Five subjects in the Compound 1 dose groups reported sevenserious AEs (3 mg BID; one subject each with pancreatitis and pulmonaryembolism, 6 mg BID; one subject with pulmonary embolism and deep veinthrombosis, one patient with TIA and benign prostate hyperplasia, 18 mgBID dose; one subject acute respiratory failure). One subject on placeboexperienced a serious AE of bronchiectasis. The overall infection rateswere similar for the Compound 1 3- and 6 mg BID dose groups and placebo(20%, 22%, and 23%, respectively), but were higher in the Compound 1 12-and 18 mg BID dose groups (40% and 38*%). No serious infections werereported in any of the Compound 1 treatment groups. Herpes zosteroccurred in two subjects in the placebo group (4%) and three subjectswho received Compound 1 (1%, one case each in the 3-, 12- and 18 mg BIDgroups; all were isolated to a single dermatome). The two reportedevents of hepatic disorders in the 18 mg BID dose group and one event inthe placebo group were attributed to increased transaminases; none wereserious. There was an adjudicated case of transient ischemic attack(left ventricular hypertrophy, classified as mild) in one subject in theCompound 1 6 mg BID group. One patient in the 6 mg BID group had oneevent each of basal cell carcinoma and squamous cell carcinoma. Therewere no opportunistic infections or deaths during the study period.

Dose-dependent increases in low-density lipoprotein cholesterol (LDL-C)and high-density lipoprotein cholesterol (HDL-C) were observed; however,the ratios of LDL-C/HDL-C remained the same through Week 12. Of thesubjects with normal AST or ALT at baseline, 6-18% of patients onCompound 1 had elevated AST at least twice, and 4-11% had elevated ALTat least twice, versus 2% and 6% on placebo, respectively. The number ofthese subjects was higher in the higher dose groups. Most of theelevations were Grade 1 (for AST and ALT, ≥1.2−≤1.6×ULN) and Grade 2(1.6-3.0×ULN). One subject each (2%) in the Compound 1 3 mg BID andplacebo group (2%) had a Grade 3 ALT elevation (3.0−8.0×ULN). Of thesubjects with normal creatinine at baseline, 4-14% subjects on Compound1 had elevated creatinine at least twice versus none in the placebogroup. One subject in the 18 mg BID group had a Grade 3 elevation(≥1.9−≤3.0×ULN). The elevations did not result in discontinuation of anysubject from the study.

Decreases from baseline in mean hemoglobin levels were observed in adose-dependent manner with Compound 1, although mean hemoglobin levelsremained within the normal range across all dose groups during the study(FIG. 3A). Twenty-six out of 219 subjects (11.9%) in the Compound 1groups had a Grade 2 decrease in hemoglobin (from 15-20 g/L); 14/219subjects (6.4%) had a Grade 3 decrease (from 21-29 g/L); 8/219 subjects(3.7%) had a Grade 4 decrease (≥30 g/L). The majority (79%) of thesedecreases were transient (only one occurrence) and one subjectdiscontinued the study due to reported AE of low hemoglobin. However, insubjects with underlying systemic inflammation, as measured by elevatedbaseline hsCRP, treatment with Compound 1 at 3- or 6 mg BID resulted inmean increases from baseline in hemoglobin levels compared with placebo(FIG. 3B).

Decreases in mean circulating leukocytes, neutrophils (Table 22D) andnatural killer (NK) cells were also observed, and one subjectdiscontinued study drug due to leukopenia. Only NK cell reductionsappeared to be dose-related. The mean percentage change in NK cells was+16.5±46.6 in the placebo group; a dose-dependent decrease was seen insubjects treated with Compound 1 (−15.8±25.3 in the 3 mg BID group,−18.3±47.4 in the 6 mg BID group, −28.0±37.3 in the 12 mg BID group, and−42.6±31.7 in the 18 mg BID group). At all doses of Compound 1, therewas a transient mean increase in total lymphocytes, which returned tobaseline level by Week 12, except in the 18 mg dose group. There weretwo subjects in the 18 mg dose group with Grade 4 lymphocyte reduction;one subject was reported to have vaginal and urinary tract infection,and the other herpes zoster. One subject had a Grade 4 neutrophilreduction, which was not associated with a serious infection.

TABLE 22C Adverse Events Summary Compound 1 3 mg 6 mg 12 mg 18 mgPlacebo BID BID BID BID AE, n (%) (n = 56) (n = 55) (n = 55) (n = 55) (n= 55) Any AE 25 (45) 26 (47) 31 (56) 37 (67) 39 (71) Any serious AE  1(2)  2 (4)  2 (4)  0  1 (2) Any severe AE  2 (4)  1 (2)  2 (4)  2 (4)  1(2) Any AE leading to  2 (4)  0  6 (11)  2 (4)  3 (5) discontinuationAny death  0  0  0  0  0 AEs of special interest Infection 13 (23) 11(20) 12 (22) 22 (40) 21(38) Serious infection  1 (2)  0  0  0  0Cardiovascular event  0  0  1 (2)^(†)  0  0 Herpes zoster  2 (4)  1 (2) 0  1 (2)  1 (2) Hepatic disorder*  1 (2)  0  0  0  2 (4) Malignancy  0 0  1 (2)^(‡)  0  0 Abbreviations: AE-adverse event; BID-twice daily,*AEs as reported by the investigator. ^(†)The cardiovascular event wasadjudicated as a transient ischemic attack. ^(‡)One patient with basalcell and squamous cell carcinoma.

TABLE 22D Mean Change Over Time in Select Hematology Parameters andIncidence of Patients With Abnormalities Compound 1 3 mg 6 mg 12 mg 18mg Abnormality, Placebo BID BID BID BID number (%) (n = 56)* (n = 55)*(n = 55)* (n = 55) (n = 55) Neutrophils × 10⁹/L Grade 2 (1.0-1.4)  1 (2) 0  3 (6)  4 (7)  7 (13) Grade 3 (0.5-0.9)  0  0  0  2 (4)  1 (2) Grade4 (<0.5)  0  0  0  1 (2)  0 Lymphocytes × 10⁹/L Grade 2 (1.0-1.4) 18(33) 14 (26) 19 (35) 14 (25) 26 (47) Grade 3 (0.5-0.9)  9 (16)  8 (15) 8 (15) 11 (20)  9 (16) Grade 4 (<0.5)  0  1 (2)  1 (2)  0  2 (4)BID-twice daily. *1 subject with missing data. Safety population.Grading based on OMERACT Rheumatology Common Toxicity Criteria v.20

Discussion

In this study, a broad dose range of Compound 1 (dosed up to 18 mg BID)was tested to assess efficacy and safety in subjects with an inadequateresponse or intolerance to anti-TNF biologic therapies. At all doses.Compound 1 demonstrated rapid and robust efficacy as shown bysignificantly greater improvements in clinical and functional outcomescompared to placebo. The onset of improvement with Compound 1 treatmentwas rapid with up to 58% of subjects achieving an ACR20 response asearly as 2 weeks after treatment. The proportion of ACR20 respondersreached a maximum at 8 weeks and plateaued at 71% through Week 12.Improvements in ACR50 (up to 42%) and ACR70 (up to 25%) response ratesin the Compound 1 groups also reached a maximum before Week 12. Thespeed of the response is in contrast to the 3-6 months observed for manybiologic therapies (Bathon, et al., The New England Journal of Medicine,2000, Vol. 343(22). pp. 1580-93; Keystone, et al., Arthritis andRheumatism, 2008. Vol. 58(11). pp. 3319-29; Keystone, et al., Arthritisand Rheumatism, 2004, Vol. 50(5), pp. 1400-11) and comparable with thatobserved for other JAK inhibitors, baricitinib and tofacitinib in TNF-IRpatients. (Burmester, et al., Lancet (London, England), 2013, Vol.381(9865), pp. 451-60, Genovese, et al., European League AgainstRheumatism, 2015; 2015). In addition, the ACR20 response rate wascomparable between subjects with two or more prior anti TNF therapiesand those with only one prior anti-TNF. In general, the maximum efficacywas observed at the 12 mg BID dose.

Despite producing significant clinical improvement in different spectraof RA patients, there are safety concerns with JAK inhibitors,predominantly around impairing the body's ability to fight infections,viral reactivation, as well as altering hematopoietic homeostasis thatcould link to anemia. The most commonly reported adverse events with JAKinhibitors are infections, herpes zoster, pulmonary tuberculosis,cryptococcal pneumonia and Pneumocystis pneumonitis (Fleischmann, etal., Arthritis Rheumatol., 2015, Vol. 67(2), pp. 334-43; Genovese, etal., Arthritis Rheumatol., 2016, Vol. 68(1), pp. 46-55). In addition,increases in total cholesterol, elevation of transaminase and serumcreatinine, decreases in neutrophil counts and anemia are also observed.(Burmester, et al., Lancet (London, England), 2013, Vol. 381(9865), pp.451-60; Genovese, et al., Arthritis Rheumatol., 2016, Vol. 68(1), pp.46-55; Keystone, et al., Annals of the Rheumatic Diseases, 2015, Vol. 174(2), pp. 33340).

In the current study, a broad range of doses of Compound 1 were testedto assess the selectivity of Compound 1 in vivo. Overall, Compound 1demonstrated an acceptable safety and tolerability profile at all dosesin this refractory RA population. There was no serious infection,although the proportion of overall infection rates was higher at the twohighest doses of Compound 1 (12 mg and 18 mg BID). The most commonlyobserved infections with Compound 1 were bronchitis, upper respiratory,and urinary tract infections. The incidence of herpes zoster was similarin the placebo group (two subjects, 4%) and the Compound 1 treatmentgroups (three subjects, 1%), and all were non-disseminated.

At the 12 mg BID and 18 mg BID doses, there was a modest decrease inmean hemoglobin levels by Week 12, although the mean hemoglobin levelsremained within the normal range. Notably, in subjects with elevatedhsCRP at baseline, who were receiving 3 or 6 mg BID Compound 1, meanhemoglobin levels increased compared to placebo treatment, possibly dueto a reduction of systemic inflammation while minimizing inhibitoryeffects on JAK2.

Circulating NK cells, which function as the critical mediator of hostimmunity against malignancy and infections, were measured as apharmacodynamic readout of IL-15 inhibition. With increasing doses ofCompound 1 there was a greater decrease in mean circulating NK cellcounts. At the maximally efficacious dose, 12 mg BID, NK cells decreasedby 28% from baseline, with proportionally smaller decreases in NK cellsobserved at lower doses. Given the fact that IL-15 signaling involves aheterodimer of JAK1 and JAK3, this was to be expected at higher doses ofCompound 1. It is unclear how much each of the heterodimeric components(JAK1 and JAK3) contributes to the overall IL-15 signaling. However, itis possible that at higher exposure of Compound 1, the threshold forin-vivo selectivity for JAK1 compared to JAK3 is lowered in the contextof the JAK1/JAK3 heterodimer. Of note, for tofacitinib at 5 mg BID, thereported median decrease in NK cells at week 24 was −35%, with greaterreduction at 10 mg BID or higher doses of tofacitinib (van Vollenhoven,et al., Annals of the Rheumatic Diseases, 2015, pp. 258-9; Addendum toPrimary Clinical Review, NDA 203.214, Center for Drug Evaluation andResearch). However, it is important to note that the significance of NKcell reduction, especially what is considered clinically meaningfulreduction in NK cells in terms of predicting clinical events (i.e. onsetof viral reactivation) is lacking. A significant association with thechanges in nadir NK cells and treated infection rates with tofacitinibtreatment was observed (van Vollenhoven, et al., Annals of the RheumaticDiseases, 2015, pp. 258-9). No association of the reduced NK cells withclinical events was observed in the current study.

As reported with other JAK inhibitors, a dose-dependent elevation of lowdensity lipoprotein cholesterol and high density lipoprotein cholesterollevels was observed with Compound 1, however, the ratio of LDL-C/HDL-Cremained unchanged. For the other laboratory parameters of interest,i.e, serum transaminases, WBC, neutrophil, or lymphocytes, the meanchanges were unremarkable and lacked apparent dose relationship, withonly one subject discontinuing the study early due to leukopenia.

In summary, the results of the current study demonstrated safety andefficacy of a selective JAK1 inhibitor, Compound 1, in adifficult-to-treat population of RA patients who had an inadequateresponse or intolerance to anti-TNF biologic therapies.

Example 33: Treatment of Moderately to Severely Active RheumatoidArthritis in Patients Who have Inadequately Responded to Methotrexate

The following example briefly describes the results of a Phase 2b,12-week, randomized, double-blind, parallel-group, placebo-controlledstudy in which adult subjects with moderately to severely activerheumatoid arthritis (RA) who have inadequately responded to stablemethotrexate therapy were treated with Compound 1.

Patients

Men and women aged ≥18 years with active RA and inadequate response tomethotrexate were included in the study. Diagnosis of RA was based onthe 1987 revised American College of Rheumatology (ACR) classificationcriteria (Arnett et al, Arthritis Rheum., 1988, Vol. 31(3), pp. 315-324)or the 2010 ACR/European League Against Rheumatism (EULAR) criteria(Smolen et al, Ann. Rheum. Dis., 2010, Vol. 69(6), pp. 964-975). ActiveRA was defined by minimum disease activity criteria of ≥6 swollen joints(based on 66 joint counts) at screening and baseline; ≥6 tender joints(based on 68 joint counts) at screening and baseline; andhigh-sensitivity C-reactive protein (hsCRP) greater than the upper limitof normal (ULN) or positive test results for both rheumatoid factor andanti-cyclic citrullinated peptide (CCP) at screening. Eligible patientshad been receiving methotrexate for ≥3 months, with a stableprescription (7.5-25 mg/week) for ≥4 weeks before baseline. Stable dosesof methotrexate were continued throughout the study. In addition, allpatients were requested to take a dietary supplement of oral folic acid(or equivalent) from 4 weeks prior to baseline and throughout studyparticipation. All other oral disease-modifying antirheumatic drugs(DMARDs) were discontinued before baseline for ≥5 times the meanterminal elimination half-life of the specific DMARD to ensure washout.High-potency opiates (e.g., oxycodone, methadone, morphine) werediscontinued ≥4 weeks before baseline. All patients had a negativetuberculosis screening assessment or, if there was evidence of a latenttuberculosis infection, completed ≥2 weeks of tuberculosis prophylaxisor had documented completion of a full course of tuberculosisprophylaxis before baseline. Patients were allowed to receivenonsteroidal anti-inflammatory drugs, acetaminophen, oral/inhaledcorticosteroids, and low-potency opiates. Patients were excluded if theyhad received JAK inhibitor therapy or any other investigational orapproved biologic RA therapy.

Treatment

Patients were randomized in a 1:1:1:1:1:1 ratio in a double-blind mannerto oral doses of Compound 1 (immediate release capsules comprisingTartrate Hydrate) 3 mg BID, 6 mg BID, 12 mg BID, 18 mg BID, or 24 mg QD(two 12 mg tablets administered at the same time), or placebo BID for 12weeks. Patients were randomized using an interactive voice/web responsesystem according to a blocked randomization schedule. Investigators,patients, and other study personnel were blinded to the treatmentassignments throughout the study. To maintain blinding, the placebo andactive treatments had an identical appearance. Patients were instructedto take their doses (6 capsules total, split into 2 batches of 3) atapproximately the same times each day.

Assessments

The primary efficacy endpoint was a ≥20% improvement in ACR criteria(ACR20) at week 12. Other endpoints included ACR50 and ACR70 responserates; change in 28-joint Disease Activity Score using C-reactiveprotein (DAS28(CRP)); change in Clinical Disease Activity Index (CDAI);the proportion of patients achieving low disease activity (LDA) orclinical remission based on DAS28(CRP) and CDAI criteria; and change inthe Health Assessment Questionnaire Disability Index (HAQ-DI). Theminimal clinically important difference (MCID) on the HAQ-DI, which is adecrease of ≥0.22, (Strand et al, 2006) was also evaluated.

Safety was evaluated during treatment and for 30 days after the lastdose of study drug on the basis of adverse events (AEs), vital signs,physical examinations, and laboratory tests. AEs were coded using theMedical Dictionary for Regulatory Activities (MeDRA), version 17.1.

Statistical Analyses

The per-protocol primary efficacy analysis was conducted in a modifiedintent-to-treat population, including all randomized patients who takeat least 1 dose of study drug, with last observation carried forward(LOCF) imputation; data were also analyzed with nonresponder imputation(NRI). Statistical tests were 1-sided with a significance level of 0.05for efficacy analyses and 2-sided with a significance level of 0.05 forall other analyses. A sample of 270 patients (45 per randomizedtreatment group) was targeted give 80% power to establish a realdifference of 30% in the primary efficacy endpoint (ACR20 response rateat week 12), assuming the response rate would be 30% in the placebogroup and 60% in at least 1 of the Compound 1 dose groups.

Results

Patients

A total of 300 patients were randomized, and 299 received placebo (n=50)or Compound 1 3 mg BID (n50), 6 mg BID (n=50), 12 mg BID (n=50), 18 mgBID (n=50), or 24 mg QD (n=49). Overall, 91% of patients completed thestudy, with similar discontinuation rates across treatment groups and noapparent relationship between Compound 1 dose and discontinuation (FIGS.5A and 5B). Demographic and clinical characteristics at baseline werebalanced among treatment groups (Table 23A). Patients were from EasternEurope (61%), Central/South America (18%), the United States (10%)Western Europe (8%), or other regions (4). Patients had a mean diseaseduration of 6.9 years and 17.7% had used 1 prior non-nethotrexate DMARD.Of note, patients with normal hsCRP could be enrolled if they werepositive for rheumatoid factor and anti-CCP antibody. Approximately 43%of patients had hsCRP values≤ULN at baseline.

TABLE 23A Baseline Characteristics and Disease Activity in Patients WithInadequate Response to Methotrexate Compound 1 3 mg 6 mg 12 mg 18 mg 24mg Placebo BID BID BID BID QD Characteristic (n = 50) (n = 50) (n = 50)(n = 50) (n = 50) (n = 49) Female, number (%) 38 (76) 40 (80) 34 (68) 41(82) 42 (84) 42 (86) Age, years, mean 55 (12) 53 (12) 55 (12) 56 (12) 55(14) 56 (12) (SD) Years since RA 5.9 (5.3) 3.9 (3.8) 7.0 (5.5) 9.3 (8.6)7.3 (7.9) 8.3 (7.1) diagnosis, mean (SD) RF positive, number 41 (82) 45(90) 46 (92) 44 (88) 41 (82) 44 (90) (%) Anti-CCP positive, 39 (78) 40(80) 45 (90) 43 (86) 40 (80) 45 (92) number (%) Methotrexate dose, 16(4) 16 (4) 16 (4) 14 (4) 15 (5) 15 (4) mg, mean (SD) Prednisolone dose,0 0 0 0 mg, mean (SD) ≥1 prior non-MTX 7 (14) 6 (12) 12 (24) 11 (22) 5(10) 12 (24) DMARD, number (%) 1 6 (12) 4 (8) 10 (20) 9 (18) 2 (4) 8(16) 2 1 (2) 2 (4) 1 (2) 1 (2) 1 (2) 3 (6) ≥3 0 0 1 (2) 1 (2) 2 (4) 1(2) Disease Activity TJC68, mean (SD) 29 (16) 27 (15) 28 (16) 28 (13) 27(15) 28 (16) SJC66, mean (SD) 19 (12) 15 (8) 19 (12) 17 (11) 17 (112) 18(13) HAQ-DI, mean (SD) 1.4 (0.7) 1.3 (0.7) 1.6 (0.7) 1.5 (0.6) 1.6 (0.6)1.5 (0.7) DAS28 (CRP), mean 5.6 (1.1) 5.5 (1.1) 5.8 (1.0) 5.6 (0.9) 5.7(0.8) 5.7 (1.0) (SD) CDAI, mean (SD) 40 (14) 38 (13) 43 (14) 39 (12) 40(13) 41 (13) hsCRP, mg/L, mean 15 (26) 11 (15) 17 (20) 11 (15) 13 (15)14 (16) (SD) hsCRP > ULN,* 27 (54) 25 (50) 31 (62) 26 (52) 28 (56) 33(67) number (%)

Efficacy

The primary per-protocol endpoint, ACR20 at week 12 (LOCF imputation),was met at every dose of Compound 1 except the lowest dose of 3 mg BID.The proportions of patients with ACR20 were 65% (P=0.153), 73% (P=0.18),82% (P=0.001), 77% (P=0.008), and 82% (P=0.001) at 3 mg BID, 6 mg BID,12 mg BID, 18 mg BID, and 24 mg QD, respectively, versus the placeboresponse rate (50%). ACR20 responses (NRI) were significantly higherwith Compound 1 at 6 mg BID (68%), 12 mg BID (80)%), and 24 mg QD (76%)versus placebo (46%; FIG. 6). Responses with more stringent criteria,i.e., ACR20 and ACR70, were achieved at week 12 by significantly higherpercentages of patients who received Compound 1 versus placebo at alldoses except 12 mg BID for ACR70 response (NRI; FIG. 6). ACR20 responserates increased over time with Compound 1 to reach mean maximum valuesat weeks 6 to 12 (FIG. 7A). ACR50 responses were significant from week 4onward and plateaued at week 8 (FIG. 7B); ACR70 responses also appearedto plateau by week 8, with some further improvements up to week 12 (FIG.7C). At the first assessment (week 2), ACR20 responses with Compound 1ranged from 30% to 44% and were significantly higher at all doses inpatients who received Compound 1 versus placebo (12%). Mean decreases inDAS28(CRP) improved over time from baseline, ranging from −2.2 to −2.6with Compound 1 at week 12, and were significantly lower compared withplacebo (−1.3) at all Compound 1 doses and every time point (FIG. 7D).

Higher percentages of patients who received Compound 1 achievedDAS28(CRP)≤3.2 or ≤2.6 compared with placebo. The DAS28(CRP) 3.2 cutoffwas achieved by a significantly higher percentage of patients (41%-52%)at all doses of Compound 1 compared with placebo (20/6); the <2.6 cutoffwas achieved by significantly higher proportions (34%-40%) with Compound1 compared with placebo (14%) at all doses except 24 mg QD (22%; FIG.8A). Similarly, CDAI≤10 was achieved by a significantly higherpercentage of patients (40%-46%) compared with placebo (20%) withCompound 1 at all doses except 24 mg QD (35%; FIG. 8B).

Improvements from baseline in ACR component scores were larger withCompound 1 compared with placebo, reaching statistical significance formost comparisons at doses of 6 mg BID and greater (Table 23B). Changesfrom baseline on the HAQ-DI at week 12 with Compound 1 ranged from −0.6to −0.8 and were significantly greater than that seen with placebo(−0.4) for all but the Compound 1 24 mg QD dose (−0.6). Numerically,more patients in the Compound 1 dose groups≥6 mg BID (69%-88%) met theMCID at week 12 compared with placebo (67%); the study was not poweredfor this analysis, and the comparisons versus placebo mostly were notstatistically significant.

TABLE 23B Mean Changes From Baseline in ACR Components at Week 12Compound 1 12 mg 18 mg Placebo 3 mg BID 6 mg BID BID BID 24 mg QD ACRComponent (n = 50) (n = 50) (n = 50) (n = 50) (n = 50) (n = 49) TJC68−14.4 −15.9 −19.2* −19.2* −17.4 −18.9* SJC66 −9.9 −12.1 −11.9 −12.7*−13.2* −13.1* Patient's assessment −19.9 −25.3 −33.8** −33.4** −34.9**−29.8* of pain Physician's global −28.0 −34.7 −43.0*** −45.6*** −36.6*−37.6* assessment of disease activity Patient's global −17.5 −26.9−31.4** −23.8 −29.1* −24.1 assessment of disease activity HAQ-DI −0.4−0.6* −0.7** −0.8*** −0.6* −0.6 HAQ-DI ≤ MCID,^(§) 30 (67), 33 (67), 34(69), 44 (88), 35 (74), 38 (78), number (%), 95% CI 53-80 54-81 57-8279-97 62-87 66-89 hsCRP −0.4 −10.5*** −8.8*** −8.9*** −7.5** −8.4***Abbreviations: ACR—American College of Rheumatology; BID—twice daily;HAQ-DI—Health Assessment Questionnaire Disability Index;hsCRP—high-sensitivity C-reactive protein; LOCF—last observation carriedforward; MCID—minimal clinically important difference; QD—once daily;RA—rheumatoid arthritis; SJC66—swollen joint count using 66 joints;TJC68—tender joint count using 68 joints. *P < 0.05; **P < 0.01; ***P <0.001 relative to placebo. ^(§)MCID = −0.22. Modified intent-to-treatpopulation with LOCF imputation of missing values. 95% CIs werecalculated based on a normal approximation to the binomial distribution.

As can be seen from these results, Compound 1 had an early onset ofaction in subjects who have demonstrated a prior inadequate response tomethotrexate. In particular, ACR20 response rates improved starting atweek 2, with a maximum effect achieved as early as week 6, withcontinued improvement in some dose groups through week 12. ACR50(maximum efficacy up to 50%) and ACR70 (maximum efficacy up to 28%)response rates also quickly plateaued by about week 8. Compound 1 showeda dose-dependent efficacy that seemed to reach a maximum at 12 mg BID.

Safety

The safety and tolerability profile of Compound 1 across doses wasacceptable (Table 23C). Incidence of any AE was statisticallysignificantly higher with Compound 1 overall versus placebo (45% vs 26%;P=0.012), with a trend of dose dependence. Among common AEs, those thatoccurred in ≥3% patients in any group were abdominal pain, abdominalpain upper, back pain, blood creatine phosphokinase increased, cough,diarrhea, dyslipidemia, dyspepsia, gastroenteritis, headache, herpeszoster, influenza, leukopenia, nasopharyngitis, upper respiratory tractinfection, urinary tract infection, white blood cell count decreased,and wound. Most AEs in the Compound 1 treatment groups were mild ormoderate in severity. Severe AEs occurred in 1 patient each withCompound 1 at 6 mg BID (lung cancer at post treatment day 10 in a79-year-old male patient with family and smoking histories; the patientdied 3 months later), 12 mg BID (pyrexia), 18 mg BID(hyperbilirubinemia), and 24 mg QD (head injury). There were 2 seriousAEs with Compound 1 that were considered possibly related to study drug:community-acquired pneumonia at 12 mg BID and syncope at 24 mg QD.Infections overall occurred in 20% of patients who received Compound 1and 14% who received placebo, with no tendency towards higher rates athigher doses. Three herpes zoster infections, 1 with Compound 1 at 3 mgBID and 2 at 24 mg QD, involved 1 dermatome per patient. A patient inthe Compound 1 6 mg BID group, aged 79 years and with a history ofsmoking, was diagnosed with lung cancer 10 days after stopping studytreatment and died 3 months later.

At week 12, mean values for alanine aminotransferase (ALT) weresignificantly higher with Compound 1 18 mg BID than with placebo; meanvalues for aspartate aminotransferase (AST) were significantly higherthan placebo with all Compound 1 doses>3 mg BID (Table 23D). However,grade 3/4 ALT or AST abnormalities during the study were sporadic, withno clear dose dependence (Table 23E). Creatinine and creatinephosphokinase levels were significantly higher in all Compound 1 dosegroups compared with placebo. Compound 1 was associated with elevationsin high-density and low-density lipoprotein cholesterol (HDL-C; LDL-C);HDL-C elevation was statistically significant at 6 mg BID, whereas LDL-Cvalues were significantly higher than placebo for all Compound 1 doses;however, the ratios of LDL-C/HDL-C remained the same through week 12.There were no significant decreases in lymphocyte or neutrophil levelsbetween placebo and Compound Idose groups by week 12. Grade 3 lymphocytevalues occurred with placebo and all doses of Compound 1; grade 4 valuesoccurred in 1 patient each with Compound 1 at 3 mg BID and 18 mg BID(Table 23E). Grade 3 neutrophil values occurred with Compound 1 at 12 mgBID (1 patient), 18 mg BID (3 patients), and 24 mg QD (1 patient).Natural killer (NK) cell percentages were significantly lower thanplacebo with Compound 1 doses≥6 mg BID (Table 23D).

Mean changes in hemoglobin over time in all patients, patients withhsCRP values≤5 mg/mL, and patients with hsCRP values>5 mg/mL are shownin FIGS. 9A-9C. Mean hemoglobin values remained stable or increased atlower doses, most notably in patients with elevated CRP at baseline.Dose-dependent decreases in hemoglobin were seen at higher doses withoutclinical impact.

TABLE 23C Adverse Events Summary Compound 1 Placebo 3 mg BID 6 mg BID 12mg BID 18 mg BID 24 mg QD AE, Number (%) (n = 50) (n = 50) (n = 50) (n =50) (n = 50) (n = 49) Overal AEs Any AE 13 (26) 19 (38) 23 (46) 29 (58)25 (50) 17 (35) Any AE possibly 6 (12) 5 (10) 6 (12) 17 (34) 11 (22) 5(10) drug related* Any serious AE 0 0 2 (4) 1 (2) 3 (6) 2 (4) Anyserious AE 0 0 0 1 (2) 0 1 (2) possibly drug related* Any severe AE 0 01 (2) 1 (2) 1 (2) 1 (2) Any AE leading to 1 (2) 1 (2) 1 (2) 1 (2) 5 (10)1 (2) discontinuation Any AE leading to 0 0 0 0 0 0 death AEs ≥3% in anygroup Abdominal pain 0 1 (2) 1 (2) 2 (4) 0 1 (2) Abdominal pain 0 0 0 2(4) 1 (2) 1 (2) upper Back pain 0 1 (2) 3 (6) 1 (2) 0 1 (2) Bloodcreatine 0 0 0 3 (6) 2 (4) 1 (2) phosphokinase increased Cough 0 1 (2) 1(2) 3 (6) 1 (2) 0 Diarrhea 0 0 1 (2) 3 (6) 1 (2) 1 (2) Dyslipidemia 0 1(2) 0 3 (6) 0 0 Dyspepsia 1 (2) 0 0 0 2 (4) 0 Gastroenteritis 0 2 (4) 00 0 1 (2) Headache 1 (2) 2 (4) 1 (2) 3 (6) 0 1 (2) Herpes zoster 0 1 (2)0 0 0 2 (4) Influenza 0 0 0 4 (8) 1 (2) 0 Leukopenia 0 0 0 3 (6) 1 (2) 0Nasopharyngitis 1 (2) 1 (2) 2 (4) 4 (8) 2 (4) 3 (6) Upper respiratory 00 1 (2) 1 (2) 2 (4) 0 tract infection Urinary tract 2 (4) 2 (4) 2 (4) 2(4) 0 2 (4) infection White blood cell 0 0 1 (2) 0 2 (4) 0 countdecreased Wound 0 0 2 (4) 0 0 0 AEs of special interest Infection 7 (14)10 (20) 7 (14) 12 (24) 11 (22) 9 (18) Serious infection 0 0 0 1 (2) 0 0Cardiovascular 0 0 0 0 0 1 (2)* event Herpes zoster^(†) 0 1 (2) 0 0 0 2(4) Hepatic disorder 0 0 0 0 2 (4) 0 Malignancy 0 0 1 (2)^(‡) 0 0 0Abbreviations: AE—adverse event; BID—twice daily; QD—once daily. *Thecardiovascular event was a cerebrovascular accident and was adjudicatedas an ischemic stroke. ^(†)The events of herpes zoster involved 1dermatome per patient. ^(‡)Lung cancer at posttreatment day 10 in a79-year-old male patient with family and smoking histories. The patientdied 3 months later.Safety analysis population.

TABLE 23D Mean Changes in Laboratory Values of Interest at Week 12Compound 1 Mean (SD) Placebo 3 mg BID 6 mg BID 12 mg BID 18 mg BID 24 mgQD Value (n = 50) (n = 50) (n = 50) (n = 50) (n = 50) (n = 49) ALT, U/L−1.3 (15.4) −1.1 (20.7) 6.5 (10.0) 7.0 (31.8) 8.5 (18.5)* 5.3 (20.7)AST, U/L −0.1 (8.4) 1.9 (11.9) 6.6 (5.5)** 7.6 (14.3)** 7.7 (11.3)** 4.8(10.9)* HDL-C, 0.01 (0.21) 0.12 (0.32) 0.17 (0.26)* 0.13 (0.30) 0.13(0.43) 0.13 (0.33) mmol/L LDL-C, −0.05 (0.43) 0.28 (0.82)* 0.34 (0.71)*0.49 (0.93)** 0.27 (0.83)* 0.32 (0.62)** mmol/L Creatinine, −0.9 (7.9)2.0 (8.2)** 4.9 (9.1)** 4.3 (7.1)** 4.6 (10.2)** 5.4 (8.5)** μmol/LCreatine −7.7 (90.1) 40.2 (46.5)* 82.5 (80.6)** 100.4 (126.5)** 108.7(140.2)** 59.4 (94.0)** phosphokinase, U/L Lymphocytes, −0.09 (0.50)0.12 (0.58) 0.01 (0.79) −0.08 (0.67) −0.12 (0.53) −0.13 (0.49) ×10⁹/LNeutrophils, −0.5 (2.20) −1.1 (2.13) −0.9 (1.60) −0.9 (1.90) −0.9 (2.16)−0.4 (1.99) ×10⁹/L NK cells, −0.1 (4.46) −1.3 (4.54) −3.1 (4.09)** −3.3(4.67)** −5.3 (4.24)** −4.9 (5.12)** CD3−/16−/56+, %^(†) Abbreviations:ALT—alanine aminotransferase; AST—aspartate aminotransferase; BID—twicedaily; HDL-C—high-density lipoprotein cholesterol; LDL-C—low-densitylipoprotein cholesterol; NK—natural killer; QD—once daily. *P < 0.05;**P < 0.01 relative to placebo; P value for difference between treatmentgroups in baseline and mean change from baseline using a contrast withinthe one-way analysis of variance. ^(†)Mean percentage change frombaseline at week 12.Safety analysis population.

TABLE 23E Incidence of Patients With Laboratory Abnormalities at Week 12Compound 1 3 mg 6 mg Placebo BID BID 12 mg BID 18 mg BID 24 mg QD (n =50) (n = 50) (n = 50) (n = 50) (n = 50) (n = 49) ALT, U/L Grade 3(3.0-8.0 × ULN) 0 1 1 2 1 0 Grade 4 (>8.0 × ULN) 0 0 0 0 1 0 AST, U/LGrade 3 (3.0-8.0 × 0 1 1 0 1 0 ULN) Grade 4 (>8.0 × ULN) 0 0 0 0 0 0Neutrophils × 10⁹/L Grade 3 (0.5-0.9) 0 0 0 1 3 1 Grade 4 (<0.5) 0 0 0 00 0 Lymphocytes, × 10⁹/L Grade 3 (0.5-0.9) 7 8 13 16 17 15 Grade 4(<0.5) 0 1 0 0 1 0 Abbreviations: ALT—alanine aminotransferase;AST—aspartate aminotransferase; BID—twice daily; QD—once daily;ULN—upper limit of normal.

As can be seen from these results, the safety and tolerability profileof Compound 1 was acceptable across doses.

Example 34: A Phase 2/3 Ankylosing Spondylitis Clinical Study(SELECT-AXIS 1)

SELECT-AXIS 1 is a multicentre, randomised, double-blind,parallel-group, placebo-controlled, Phase 2/3, two-period study ofupadacitinib (FIG. 10), 15 mg upadacitinib refers to the 15 mgonce-daily (QD) upadacitinib Extended Release (ER) Wet GranulatedTablets drug product as described herein are provided in the followingTable 24A. The 15 mg upadactinib ER tablet (or matching placebo) istaken orally once daily, beginning on Day 1 (Baseline), and should betaken at approximately the same time each day, with or without food.

TABLE 24A Upadacitinib 15 mg Extended Release (ER) Tablets (WetGranulated) Component Function Weight Tablet Core IntragranularUpadacitinib* Drug substance 15.4 Microcrystalline cellulose Filler 41.2(≥65% through 75 um screen) (Avicel PH 102) Hypromellose 2208 Controlrelease 4.9 polymer and binder Purified water Wetting agent N/AExtragranular Microcrystalline cellulose Filler 121.3 (≥65% through 75um screen) (Avicel PH 102) Mannitol (Pearlitol 100 SD) Filler 100.6Tartaric acid powder pH modifier 96.0 Hypromellose 2208 Control release91.1 polymer Colloidal Silicon Dioxide Glidant 7.4 Magnesium StearateLubricant 7.2 Film Coat OPADRY II Yellow (PVA, TiO₂, Film coat 14.40PEG3350, Talc. Iron Oxide Yellow) Purified water** Processing Aid N/A*hemillydrate upadacitinib free base Form C as disclosed in WO2017066775and WO 2018/165581 is used. 15 mg amount per tablet refers to the amountof anhydrous upadacitinib free base in the tablet; **removed duringprocessing.

Period 1 is the 14-week randomized, double-blind, parallel-group,placebo-controlled period designed to compare the safety and efficacy ofupadacitinib free base 15 mg QD (once daily) versus placebo for thetreatment of signs and symptoms of subjects with active AS who have hadan inadequate response to at least two NSAIDs over an at least 4-weekperiod in total at maximum recommended or tolerated doses or intoleranceto or a contraindication for NSAIDs, and who are biologic DiseaseModifying Anti-Rheumatic Drug (bDMARD)-naïve.

Period 2 is an open label long-term extension to evaluate the long-termsafety, tolerability, and efficacy of upadacitinib free base 15 mg QD insubjects with AS who have completed Period 1.

X-rays of the pelvis were performed within the 35-day screening periodto evaluate the SI joints to confirm the fulfillment of the modified NewYork Criteria for AS. X-rays of the spine were also performed within the35-day screening period to assess for total spinal ankylosis; subjectswith total spinal ankylosis were not eligible for this study. The x-raysof the spine and pelvis were not required during the Screening Period ifthe subject had a previous anteroposterior (AP) pelvis x-ray and lateralspine x-rays within 90 days of the Screening Period, provided that thex-rays are confirmed to be adequate for the required evaluations and aredeemed acceptable by the central imaging vendor.

Subjects who met eligibility criteria were randomized in a 1:1 ratio toone of two treatment groups:

-   -   Group 1: Upadacitinib free base 15 mg QD. N=85 (Day 1 to Week        14)→Upadacitinib free base 15 mg QD (Week 14 and thereafter)    -   Group 2: Placebo. N=85 (Day 1 to Week 14)→Upadacitinib free base        15 mg QD (Week 14 and thereafter)

Starting at Week 16, subjects who did not achieve at least an ASAS 20response at two consecutive visits had the option to add or modify dosesof NSAIDs, acetaminophen/paracetamol, low potency opioid medications(tramadol or combination of acetaminophen and codeine or hydrocodone),and/or modify dose of MTX or SSZ at Week 20 or thereafter.

Starting at Week 24, subjects who still did not achieve at least an ASAS20 response at two consecutive visits were discontinued from study drugtreatment.

Subjects who completed the Week 14 visit (end of Period 1) entered theopen-label long-term extension portion of the study, Period 2 (90weeks). Subjects who were assigned to Upadacitinib in Period 1 continuedto receive Upadacitinib free base 15 mg QD in an open-label manner.Subjects who were randomized to placebo at Baseline also receivedopen-label upadacitinib free base 15 mg QD at Week 14.

Main Inclusion Criteria:

-   1 Male or female ≥18 years of age.-   2 Subject with a clinical diagnosis of AS and meeting the modified    New York Criteria for AS.-   3 Subject must have baseline disease activity as defined by having a    Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score≥4    and a Patient's Assessment of Total Back Pain score (Total Back Pain    score)≥4 based on a 0-10 Numeric Rating Scale (NRS) at the Screening    and Baseline Visits.-   4 Subject has had an inadequate response to at least two NSAIDs over    an at least 4-week period in total at maximum recommended or    tolerated doses, or subject has an intolerance to or    contraindication for NSAIDs.-   5. If entering the study on concomitant methotrexate (MTX),    leflunomide, sulfasalazine (SSZ), and/or hydroxychloroquine, subject    must be on a stable dose of MTX (≤25 mg/week) and/or SSZ (≤3 g/day)    and/or hydroxychloroquine (≤400 mg/day) or leflunomide (≤20 mg/day)    for at least 28 days prior to the Baseline Visit. A combination of    up to two background conventional-synthetic disease modifying    anti-rheumatic drugs (csDMARDs) is allowed EXCEPT the combination of    MTX and leflunomide.-   6 If entering the study on concomitant oral corticosteroids, subject    must be on a stable dose of prednisone (≤10 mg/day), or oral    corticosteroid equivalents, for at least 14 days prior to the    Baseline Visit.-   7 If entering the study on concomitant NSAIDs, tramadol, combination    of acetaminophen and codeine or hydrocodone, and/or non-opioid    analgesics, subject must be on stable dose(s) for at least 14 days    prior to the Baseline Visit.

Main Exclusion Criteria:

-   1 Patients with total spinal ankylosis were ineligible.-   2 Prior exposure to any Janus kinase (JAK) inhibitor (including but    not limited to tofacitinib, baricitinib, and filgotinib).-   3 Prior exposure to any biologic therapy with a potential    therapeutic impact on spondyloarthritis (SpA).-   4 Intra-articular joint injections, spinal/paraspinal injection(s),    or parenteral administration of corticosteroids within 28 days prior    to the Baseline Visit. Inhaled or topical corticosteroids are    allowed.-   5. Subject on any other DMARDs (other than those allowed),    thalidomide, or apremilast within 28 days or five half-lives    (whichever is longer) of the drug prior to the Baseline Visit.-   6 Subject on opioid analgesics (except for combination    acetaminophen/codeine or acetaminophen/hydrocodone which are    allowed) or use of inhaled marijuana within 14 days prior to the    Baseline Visit.-   7 Subject has a history of inflammatory arthritis of different    etiology other than axial SpA (including but not limited to    rheumatoid arthritis [RA], psoriatic arthritis [PsA], mixed    connective tissue disease, systemic lupus erythematosus, reactive    arthritis, scleroderma, polymyositis, dermatomyositis,    fibromyalgia), or any arthritis with onset prior to 17 years of age.

Primary Endpoint

The primary efficacy endpoint is ASAS 40 response at Week 14.

Key Secondary Endpoints

The key multiplicity adjusted secondary efficacy endpoints at Week 14are:

-   -   1. Change from Baseline in Ankylosing Spondylitis Disease        Activity Score (ASDAS(CRP));    -   2. Change from Baseline in MRI Spondyloarthritis Research        Consortium of Canada (SPARCC) score (Spine);    -   3. Proportion of subjects with BASDAI 50 response (defined as        50% improvement in the Bath AS Disease Activity Index);    -   4. Change from Baseline in AS quality of life (ASQoL);    -   5. Proportion of subjects with ASAS partial remission (PR)        (defined as an absolute score of ≤2 units for each of the four        domains identified in ASAS 40);    -   6. Change from Baseline in BASFI;    -   7. Change from Baseline in BASMI_(lin);    -   8. Change from Baseline in Maastricht Ankylosing Spondylitis        Enthesitis Score (MASES) (i.e., for subjects with baseline        enthesitis);    -   9. Change from Baseline in Work Productivity and Activity        Impairment (WPAI) (the overall work impairment due to SpA);    -   10. Change from Baseline in ASAS HI.    -   Additional key secondary endpoints are:    -   11. ASAS 20 response at Week 14.    -   12. Change from Baseline in MRI SPARCC score (SI joints) at Week        14.

Additional endpoints are the following measurements assessed in subjectstreated with upadacitinib versus placebo at scheduled time points otherthan those specified for the primary and key secondary variables:

-   -   1. Proportion of subjects with ASAS 20 response;    -   2. Proportion of subjects with ASAS 40 response;    -   3. Proportion of subjects with ASAS PR;    -   4. Proportion of subjects with ASAS 5/6 (20% improvement from        Baseline in five out of the following six domains: BASFI,        patient's assessment of total back pain, PtGA, inflammation        [mean of Questions 5 and 6 of the BASDAI] lateral lumbar flexion        from BASMIlin, and high sensitivity CRP [hsCRP]);    -   5. Proportion of subjects with Inactive Disease based on        ASDAS(CRP) and ASDAS (ESR) (ASDAS score<1.3);    -   6. Proportion of subjects with Major Improvement based on        ASDAS(CRP) and ASDAS (ESR) (a change from Baseline≤−2.0);    -   7. Proportion of subjects with Clinically Important Improvement        based on ASDAS(CRP) and ASDAS (ESR) (a change from        Baseline≤−1.1);    -   8. Proportion of subjects with Resolution of dactylitis (i.e.,        for subjects with baseline presence of dactylitis);    -   9. Change from Baseline in ASAS HI;    -   10. Change from Baseline in ASDAS(CRP) and ASDAS (ESR)        respectively;    -   11. Change from Baseline in AsQoL;    -   12. Change from Baseline in BASDAI;    -   13. Change from Baseline in BASFI;    -   14. Change from Baseline in BASMIlin;    -   15. Change from Baseline in CRP;    -   16. Change from Baseline in Total dactylitis count (i.e., for        subjects with baseline presence of dactylitis);    -   17. Change from Baseline in FACIT-F;    -   18. Change from Baseline in ISI;    -   19. Change from Baseline in MASES (i.e., for subjects with        baseline MASES>0);    -   20. Change from Baseline in Modified Stoke Ankylosing        Spondylitis Spine Score (mSASSS) score with conventional        radiograph;    -   21. Change from Baseline in MRI SPARCC score of SI joints;    -   22. Change from Baseline in MRI SPARCC score of Spine;    -   23. Change from Baseline in Patient's Assessment of Total Back        Pain NRS score 0-10;    -   24. Change from Baseline in Patient's Assessment of Nocturnal        Back Pain NRS score 0-10;    -   25. Change from Baseline in Patient's Global Assessment of Pain        NRS score 0-10;    -   26. Change from Baseline in Physician's Global Assessment of        Disease Activity NRS score 0-10;    -   27. Change from Baseline in Inflammation (mean of Questions 5        and 6 of BASDAI NRS scores 0-10);    -   28. Change from Baseline in Patient's assessment of total back        pain (BASDAI Question 2 NRS score 0-10);    -   29. Change from Baseline in Peripheral pain/swelling (BASDAI        Question 3 NRS score 0-10);    -   30. Change from Baseline in Duration of morning stiffness        (BASDAI Question 6 NRS score 0-10);    -   31. Change from Baseline in Patient's Global Assessment of        Disease Activity NRS score 0-10;    -   32. Change from Baseline in TJC68 and SJC66;    -   33. Change from Baseline in WPAI (all 4 dimension scores);    -   34. Change from Baseline in Categories in ISI. See, e.g.,        Machado et al., Ann Rheum Dis (2018) 77: 1539-40; Maksymowych et        al., Arthritis Rheum (2005) 53: 502-9.

Analysis Windows

For each protocol-specified study visit, a target study day will beidentified to represent the corresponding visit along with a windowaround the target day. Windows will be selected in a non-overlappingfashion so that a collection date does not fall into multiple visitwindows. If a subject has two or more actual visits in one visit window,the visit closest to the target day will be used for analysis. If twovisits are equidistant from the target day, then the later visit will beused for analysis.

Statistical Analyses

The planned sample size of 170 for this study (with 1:1 randomisationratio) was determined to provide ≥90% power for detecting a 26%difference in ASAS40 response rate (assuming a placebo ASAS40 responserate of 20%). Power and sample size calculations were performed at atwo-sided significance level of 0-05 accounting for a 10% dropout rate.The full analysis set included all randomised patients who received atleast one dose of study drug. The safety analysis set included allpatients who received at least one dose of study drug. The SPARCC MRIassessment population was pre-specified in the statistical analysis plan(baseline included MRI data ≤3 days after first dose of study drug, andweek 14 included MRI data up to first dose of Period 2 study drug; firstdose in Period 2 was at week 14). A supplemental post hoc SPARCC MRIanalysis was conducted to include all MRI data collected at nominalvisits at baseline and week 14. Cumulative probability plots weregenerated to illustrate MRI SPARCC score changes on a patient level.

In the full analysis set, the primary endpoint was compared between theupadacitinib and the placebo group using the Cochran-Mantel-Haenszeltest, adjusting for the stratification factor of screening hsCRP level.Non-responder imputation was used for handling missing data. Similaranalyses as for the primary endpoint were conducted for secondaryefficacy binary endpoints. For continuous secondary efficacy endpoints,comparisons between the upadacitinib and the placebo group wereperformed using mixed model for repeated measures with treatment group,visit, and treatment-by-visit interaction as fixed effects and thecorresponding baseline value and the stratification factor of screeninghsCRP level as the covariates. In order to preserve the overall type Ierror rate at α=0.05 level, a step-down approach was used to test theprimary and multiplicity-controlled key secondary endpoints. The testingsequence includes a group of endpoints tested by the Hochberg procedure,including BASDA150. ASQoL, ASAS PR, BASFI, BASMI, MASES, and WPAI (FIG.11). See, e.g., Hochberg Y, Tamhane A C. Multiple comparison procedures:John Wiley & Sons, Inc., 1987.

Week 14 Results

Between Oct. 24, 2017, and Sep. 10, 2018, 395 patients were assessed foreligibility, and 187 were enrolled into the study. Of the 395 patientsscreened, 208 (52.7%) did not meet eligibility criteria and wereexcluded from the study (main reason for screening failure was notmeeting the radiographic criterion of the modified New York criteria forAS). The remaining 187 patients who met eligibility criteria wererandomised to placebo (n=94) or upadacitinib (n=93). Overall, 95.2% ofpatients completed Period 1 through week 14 on study drug (placebo,89/94 [94.7%]; upadacitinib, 89/93 [95.7%]); one patient in the placebogroup discontinued study drug but completed Period 1 visits. The mostcommon primary reason for study drug discontinuation by week 14 wereadverse events in the placebo group (n=[13.2%]) and adverse events (n=2[2.2%]) and withdrawal of consent (n=2 [2.2%]) in the upadacitinibgroup.

Mean age was 45.4 years, mean duration from onset of symptoms was 14.4years, and mean duration since diagnosis was 6.9 years. Most patientswere male (132 [70.6%]), were human leukocyte antigen (HLA) B27 positive(143 [76.5%]) and were receiving concomitant NSAIDs at baseline (150[80.2%]. Baseline disease characteristics were generally balancedbetween the two groups. Key demographics and baseline characteristics ofthe patients are summarized in the below Table 24B.

TABLE 24B Key demographics and baseline characteristics of patientsUpadacitinib Key Demographic and Baseline PLACEBO 15 mg qdCharacteristics Mean (SD) or a (%) N = 94 n = 93 Male 69 (73.4) 63(67.7) Age (Yrs) 44 (12.1) 47 (12.8) HLA-B27 Positive 73 (77.7) 70(75.3) White 76 (80.9) 79 (84.9) Region North America 10 (10.6) 9 (9.7)South/Central America 0 0 Western Europe 33 (35.1) 30 (32.3) EasternEurope 34 (36.2) 36 (38.7) Asia^(a) 14 (14.9) 12 (12.9) Other^(b) 3(3.2) 6 (6.5) Duration of AS Diagnosis (Yrs) 6.0 (6.79) 7.8 (10.64)Duration of AS Symptom (Yrs) 14.0 (9.86) 14.8 (11.64) NSAID Use atBaseline 80 (85.1) 70 (75.3) Prior NSAID Use 94 (100) 92 (98.9) csDMARDsUse at Baseline 17 (18.1) 13 (14.0) BASDAI 6.5 (1.56) 6.3 (1.76) Totalback pain (NRS 0-10) 6.7 (1.78) 6.8 (1.77) Patient Global Assessment(NRS 0-10) 6.8 (1.66) 6.6 (1.81) ASDAS (CRP) 3.7 (0.74) 3.5 (0.76) BASFI(Function) 5.5 (2.17) 5.4 (2.36) BASMI (Mobility) 3.5 (1.48) 3.7 (1.45)Presence of Enthesitis (MASES > 0) 55 (58.5) 54 (58.1) MASES Score^(c)3.7 (2.71) 3.9 (2.79) MRI Spine SPARCC^(d) 11.9 (14.52) 10.4 (14.36) MRISacroiliac Joint SPARCC^(d) 5.4 (8.55) 7.9 (10.91) hsCRP at Screening(mg/L) 11.7 (11.11) 9.6 (12.57) hsCRP > ULN at Screening 68 (72.3) 67(72.11) AS QoL 10.3 (4.65) 10.0 (5.27) WPAI-Overall Work Impairment^(e)53.3 (24.64) 54.3 (28.10) ASAS Health Index 8.2 (3.84) 8.6 (4.12)^(a)South Korea and Japan. ^(b)New Zealand and Australia. ^(c)Summarizedfor subjects with presence of enthesitis at baseline. ^(d)Summarized forsubjects whose baseline MRI data up to 3 days post first dose of studydrug. ^(e)Summarized for subjects employed at baseline.

The study met its primary endpoint, with statistically significantlymore patients treated with upadacitinib versus placebo achieving ASAS40response at week 14 (48/93 [51.6%] vs 24/94 [25.5%]; p=0.0003) with atreatment difference (95% CI) of 26.1% (12.6-39.5%) (FIG. 12A). Asignificant difference for upadacitinib versus placebo in ASAS40 (FIG.13A) and the mean change for each of its four individual domains (FIGS.12B-12E) was observed as early as the first post-baseline visit (week2), and this difference was maintained consistently through week 14,with week 14 achieving a statistically significant difference in themultiplicity-controlled analysis. Accounting for multiplicityadjustment, change from baseline to week 14 in ASDAS (CRP) (FIG. 12C),SPARCC MRI spine (FIG. 12B), and BASH (FIG. 12C) and proportion ofpatients who achieved BASDAI50 (FIG. 12A) and ASAS PR (FIG. 12A) werestatistically significant for upadacitinib versus placebo. Upadacitinibversus placebo mean (95% CI) change from baseline to week 14 was −1.45(−1.62 to −1.28) versus −0.54 (−0.71 to −0.37; treatment difference,−0.91[−1.14 to −0.68, p<0.0001]) for ASDAS (CRP) and −2.29 (−2.73 to−1.85) versus −1.30 (−1.74 to −0.86; treatment difference, −1.00 [−1.60to −0.39, p=0.0013]) for BASFI. BASDAI50) was achieved by 42/93 (45.2%)patients treated with upadacitinib versus 22/94 (23.4%) patients in theplacebo group (treatment difference, 21.8% [8.5-35.0%; p=0.0016]) andASAS PR was achieved by 18/93 (19.4%) patients in the upadacitinib groupversus 1/94 (1.1%) in the placebo group (treatment difference, 18.3%[10.0-26.6%; p<0.001]).

For the other multiplicity-controlled key efficacy endpoints,statistical significance based on multiplicity adjustment was not metper the Hochberg procedure. Consistent improvement was observed inpatients receiving upadacitinib versus placebo with nominal pvalues<0.05 for MASES (p=0.0488), BASMI (p=0.0296). ASQoL (p=0.0156),and ASAS HI (p=0.0073) at week 14, except for WPAI (FIG. 12C).

The additional key secondary efficacy endpoints. ASAS20 and SPARCC MRISI joint score, also improved with upadacitinib versus placebo based onnominal p values (FIGS. 12A and 12B). ASAS20 was achieved by 60/93(64.5%) patients treated with upadacitinib versus 38/94 (40.4%) ofpatients in the placebo group at week 14 (treatment difference, 24.1%[10.2-38.0%; p=0.0010]).

For the SPARCC MRI outcomes, change from baseline to week 14 in SPARCCMRI spine was −6.93 (−8.58 to −5.28) for upadacitinib versus −0.22(−2.01 to 1.57) for placebo (treatment difference, −6.71 [−9.01 to−4.41; significant in multiplicity-controlled analysis, p<0.0001]) andchange from baseline to week 14 in SPARCC MRI SI joint was −3.91 (−5.05to −2.77) for upadacitinib versus −0.22 (−1.47 to −1.04) for placebo(treatment difference, −3.69 [−5.31 to −2.08; p<0.001]; FIG. 12B). Thesupplemental MRI analysis conducted in all patients with available dataconfirmed the results of the primary SPARCC MRI analysis for both thespine and SI joints (FIG. 14). The cumulative probability plots ofchange in SPARCC scores demonstrated that SPARCC MRI spine and SI jointscores improved from baseline to week 14 to a greater extent in patientsreceiving upadacitinib compared with placebo; results for the primaryMRI analyses (FIG. 15A-15B) and supplemental MRI analyses (FIG. 15C-15D)were consistent. Table 24C below summarizes the primary and keysecondary efficacy endpoints at Week 14. Table 24D below providesadditional efficacy measurements at Week 14.

TABLE 24C Primary and Key Secondary Efficacy Endpoints at Week 14^(a)Upadacitinib PLACEBO 15 mg qd Endpoint N = 94 N = 93 Primary ASAS4025.5% 51.6% Multiplicity ASDAS(CRP) −0.54 1.45 Adjusted MRI SpineSPARCC^(b) −0.22 −6.93 Key BASDAI50 23.4% 45.2% Secondary AS QoL −2.7−4.2 ASAS Partial 1.1% 19.4% Remission BASFI (Function) −1.30 −2.29BASMI (Mobility) −0.1 −0.4 MASES (Enthesitis)^(c) −1.4 −2.3 WPAI-OverallWork −12.6 −18.1 Impairment^(d) ASAS Health Index −1.4 −2.8 Other KeyASAS20 40.4% 64.5% Secondary MRI SI Joints −0.22 −3.91 SPARCC^(c)^(a)Results for binary endpoints are based on NRI analysis. Analyses forall continuous endpoints are for the change from baseline value. Resultsfor continuous endpoints are based on MMRM or ANCOVA analysis.^(b)Summarized for subjects whose baseline MRI data up to 3 days postfirst dose of study drug and week 14 data up to the first dose of period2 study drug. ^(c)Summarized for subjects with presence of enthesitis atbaseline. ^(d)Summarized for subjects employed at baseline

The proportions of patients who achieved ASDAS LDA, ASDAS ID. ASDAS CII,and ASDAS MI were greater (nominal p<0.0001) for upadacitinib versusplacebo at week 14 (FIG. 16A). These results are summarized in the belowTable 24D. Improvement in the mean ASDAS (FIG. 161B) and the individualASDAS components (FIGS. 17A-17D) was seen as early as week 2 withcontinued improvement up to week 14 with upadacitinib.

TABLE 24D Additional Efficacy Measurements at Week 14 UpadaeitinibPLACEBO 15 mg qd Endpoint (N = 94) (N = 93) ASDAS ID   0% 16.1% ASDASLDA^(a) 10.6% 49.5% ASDAS MI  5.3% 32.3% ASDAS CII 18.1% 52.7%^(a)post-hoc analysis

Patients treated with the upadacitinib 15 mg QD dose showed greaterimprovement in back pain as assessed by the Total Back Pain component ofASAS response compared to placebo at Week 14. Improvement in the overalllevel of neck, back, or hip pain was demonstrated using BASDAI Question2. Improvements were also demonstrated for peripheral pain and swelling(assessed by BASDAI question 3 on overall pain in joints other than inthe neck, back, or hips) and nocturnal back pain. Improvements in totaland nocturnal back pain were observed as early as Week 2.

No serious infections, herpes zoster, malignancy, venous thromboembolicevents, or deaths were reported in Period 1. The proportion of patientswith adverse events was higher in the upadacitinib group 58/93 (62.4%)versus placebo group 52/94 (55.3%). One serious adverse event in eachgroup was reported during Period 1: cardiovascular disorder/circulationdysregulation in the placebo group (patient was not feeling well and washospitalised but no significant findings were obtained) and worsening ofspinal osteoarthritis in the upadacitinib group in a patient with ahistory of spondylosis and disc protrusion in the cervical spine. Theproportion of patients with adverse events leading to discontinuation ofstudy drug (upadacitinib, 2/93 [2.2%]; placebo, 3/94 [3.2%]) andinfections (upadacitinib, 19/93 [20.4%]; placebo, 26/94 [27.7%]) wassimilar for both treatment groups. The most common adverse event inpatients in the upadacitinib group was blood creatine phosphokinase(CPK), which increased (8/93 [8.6%] vs 2/94 [2.1%] patients in theplacebo group), with four events (vs one with placebo) assessed by theinvestigator to be possibly related to study drug; all patients wereasymptomatic with elevations <4×ULN, except for one patient in theplacebo group with muscle pain and an increase to 4.3×ULN. Most of theseevents were reversible without study drug interruption (6/8 withupadacitinib, 1/2 with placebo). One patient in the upadacitinib groupwho already had grade 2 neutropenia at baseline experienced a mildadverse event of grade 2 neutropenia.

Seven patients reported hepatic disorder adverse events (upadacitinib,5/93 [5.4%]; placebo, 2/94 [2.1%]); none resulted in study drugdiscontinuation, and all were asymptomatic alanine aminotransferase oraspartate aminotransferase increases, with associated elevations <2×ULNin 6/7 and an elevation<3×ULN in the remaining patient. No differencesin mean haemoglobin levels were observed throughout the 14-week periodin either group.

Increases from baseline to week 14 in low-density lipoproteincholesterol (0.318 mmol/L) and high-density lipoprotein (HDL)cholesterol (0.263 mmol/L) were observed in the upadacitinib groupversus the placebo group (−0.083 and 0.010 mmol/L, respectively);however, no changes in the total cholesterol/HDL ratio were observed(upadacitinib, −0.071 mmol/L; placebo, −0.083 mmol/L).

Week 14 Results Discussion

The SELECT-AXIS 1 is the first clinical trial of upadacitinib in AS anddemonstrated consistent efficacy results supported bymultiplicity-controlled endpoints. The study met its primary endpoint ofASAS40 response at week 14 (51.6% vs 25.5%) as well as severalmultiplicity-controlled secondary endpoints reflecting statisticallysignificant improvement in disease activity (ASAS PR, BASDAI50, ASDAS),function (BASFI), and MRI outcomes (SPARCC MRI spine). The othermultiplicity-controlled secondary endpoints did not meet significance inthe multiplicity testing but demonstrated consistent improvements forASQoL, BASMI, MASES, and ASAS HI, with upadacitinib versus placebo(nominal p<0.05), with the exception of WPAI.

A rapid onset of response to upadacitinib free base 15 mg QD treatmentwas observed for ASAS40 and ASDAS composite scores and their individualdomains of disease activity (e.g., back pain, PtGA, morning stiffness,function, and serum markers of inflammation [hsCRP]), with responsesobserved as early as week 2 (first post-baseline visit) and consistentlymaintained through week 14. The results of upadacitinib on improving thesigns and symptoms of AS are further confirmed by a significantreduction of active inflammation on MRI for both the spine and the SIjoints.

In addition, outcomes related to clinically relevant treatment goals ofremission or low disease activity, such as ASDAS ID or LDA, were alsoachieved, with 50% of patients reaching ASDAS LDA (difference vsplacebo, 39%). See, e.g., Smolen et al., Ann Rheum Dis 2018; 77: 3-17.Of note, the placebo response rates for ASAS20 and ASAS40 in this studywere similar to rates observed in recent clinical studies of AS;differences in ASAS40 response with upadacitinib versus placebo werep<0.05 (based on nominal p values) as early as week 2 and maintainedthroughout 14 weeks. See e.g., van der Heijde et al., Ann Rheum Dis2017; 76: 1340-47; van der Heijde et al., Lancet 2018; 392: 2378-87; vander Heijde et al., Lancet 2018; 392: 2441-51; Landewe et al., Ann RheumDis 2014; 73: 3947. Interestingly, mean changes from baseline to week 14in the MRI SPARCC scores for the spine and SI joints in the placebogroup were quite small.

The study results are in line with findings from two Phase 2/3 JAKinhibitor studies in patients with active AS. See, e.g., van der Heijdeet al., Ann Rheum Dis 2017; 76: 134047; van der Heijde et al., Lancet2018; 392: 2378-87. Together with these findings, the SELECT-AXIS 1results further support that JAK inhibitors could represent an effectivetreatment option for AS. Currently, only TNF-α and IL-17 inhibition havebeen proven to be effective in axSpA; but, these cytokines are notdirectly blocked by JAK inhibitors including upadacitinib. See. e.g.,Furst and Louie, Arthritis Res Ther 2019; 21: 135. However, emergingdata from upadacitinib RA studies suggest that selective inhibition ofJAK1 may result in the secondary inhibition of additional pathways thatdo not depend on JAK1 signalling, such as TNF-α and IL-12. See, e.g.,Somasse et al., Ann Rheum Dis 2019; 78: 365-66. Also, otherJAK1-associated pathways, including IL-7 and IL-22, have been describedin preclinical studies, but further research is needed to evaluate themechanism of action of JAK inhibitors in axSpA. See, e.g., Veale et al.,Rheumatology (Oxford) 2019; 58: 197-205; Gracey et al., Ann Rheum Dis2016; 75: 2124-32.

The proportion of patients with adverse events was generally similar inthe upadacitinib and placebo groups, and no new safety findings wereobserved compared with previous upadacitinib phase 3 RA studies. See,e.g., Burmester et al., Lancet 2018; 391: 2503-12: Genovese et al.,Lancet 2018; 391: 2513-24; Fleischmann R, Pangan A L, Song I, et al.Upadacitinib versus placebo or adalimumab in patients with rheumatoidarthritis and an inadequate response to methotrexate: results of a phase3, double-blind, randomized controlled trial. Arthritis Rheumatol 2019;doi: 10.1002/art.41032. [Epub ahead of print]; Cohen et al., Ann RheumDis (2019) 78. No serious infections, malignancies, anaemia,lymphopenia, herpes zoster, renal dysfunction, adjudicated major adversecardiovascular events, venous thromboembolic events, or deaths werereported, and haemoglobin levels remained consistent throughout thestudy.

A higher proportion of patients in the upadacitinib group experiencedadverse events of CPK elevation, all of which were asymptomatic and mostwere mild and reversible without study drug interruption. One patient inthe placebo group experienced symptoms (muscle pain) in the setting ofelevated CPK and permanently discontinued study drug. In the twoprevious JAK inhibitor studies, elevations in CPK were also observed.See e.g., van der Heijde et al., Ann Rheum Dis 2017; 76: 1340-47; vander Heijde et al., Lancet 2018; 392: 2378-87. Additional data are neededto better understand the safety profile of upadacitinib in axSpA.

JAK inhibitors, such as upadacitinib, could help address the unmet needin axSpA treatment given that only approximately half of bDMARD-naïvepatients achieve an ASAS40 response and even less achieve remission withTNF or IL-17 inhibitor treatment. See, e.g., Sieper et al., Ann RheumDis 2017: 76: 571-92; Deodhar et al., Arthritis Rheumatol 2019; 71:599-611; van der Heijde et al., Lancet 2018; 392: 2441-51; Landewe etal., Ann Rheum Dis 2014; 73: 3947; Lie E et al., Ann Rheum Dis 2011; 70:157-63; Glintborg et al., Ann Rheum Dis 2013; 72: 1149-55. Furthermore,fewer patients are expected to achieve the treatment goal of sustainedremission/LDA, and response rates are even lower in patients with AS whohave not responded to bDMARD therapy. See, e.g., Sieper et al., Lancet2017; 390: 73-84; Sieper et al., Ann Rheum Dis 2017; 76: 571-92; Deodharet al., Arthritis Rheumatol 2019; 71: 599-611. Furthermore, somepatients with axSpA may not be eligible for or might havecontraindications common to IL-17 and TNF inhibitor therapy, such asallergic reactions and injection site pain, or specific to TNFinhibitors, such as congestive heart failure and concomitantdemyelinating disease. See. e.g., Cortese et al., Mult Scler RelatDisord 2019; 35: 193-95. The use of IL-17 inhibitors is also notrecommended for patients with concomitant inflammatory bowel disease.See, e.g., van der Heijde et al., Ann Rheum Dis 2017; 76: 978-91;Fragoulis et al., World J Gastroenterol 2019; 25: 2162-76. Becausepatients with AS are typically younger and may have more activelifestyles, a treatment option administered orally may be particularlyimportant in this patient population. See e.g., Alten et al., PatientPrefer Adherence 2016; 10: 2217-28. Considering these unmet needs, thefindings of the SELECT-AXIS 1 study, which demonstrated thatupadacitinib treatment effects are within the range observed withbDMARDs and other JAK inhibitors in AS, support further investigation ofupadacitinib for AS. See, e.g., Sieper et al., Ann Rheum Dis 2017; 76:571-92; Deodhar et al., Arthritis Rheumatol 2019; 71: 599-611; van derHeijde et al., Ann Rheum Dis 2017; 76: 134047; van der Heijde et al.,Lancet 2018; 392: 2378-87; van der Heijde et al., Lancet 2018; 392:2441-51; Landewe et al., Ann Rheum Dis 2014; 73: 39-47.

This study is not without limitations. The focus on patients with AS whowere bDMARD-naive allowed for a focused evaluation of benefit and riskin a homogeneous population, but the safety and efficacy of upadacitinibin patients with AS who are bDMARD-IR or in patients withnon-radiographic axSpA has not yet been evaluated, and further studiesare needed in these patient populations. Furthermore, only one dose ofupadacitinib was evaluated in this study, and thus there are no data toconfirm whether a higher dose could have resulted in greater efficacy.Lastly, only 14-week, short-term data are reported here, but thelong-term efficacy and safety of upadacitinib will be collected in theongoing SELECT-AXIS 1 extension period for up to 2 years.

In conclusion, oral upadacitinib free base 15 mg QD significantlyimproved disease activity, function, and MRI-detected axial inflammationin patients with active AS after 14 weeks of treatment. The incidence ofadverse events was similar with upadacitinib and placebo, and no newsafety signals were observed compared with previous studies in RA.Overall, these results support the further investigation of upadacitinibfor the treatment of AS/axSpA.

Year 1 Results

The phase 2/3 SELECT-AXIS 1 study included a randomized,placebo-controlled, 14-week period followed by 90-week open-labelextension; reported here are data through week 64.

The study enrolled adults (≥18 years) with active AS who had aninadequate response to ≥2 non-steroidal anti-inflammatory drugs therapy(or intolerance to or contraindication for NSAIDs) and were biologicdisease-modifying antirheumatic drugs naïve, and who met the modifiedNew York criteria based on independent central reading of radiographs ofthe sacroiliac joints and who had active disease at baseline defined asBath Ankylosing Spondylitis Disease Activity Index (BASDAI) score≥4 andpatient's assessment of back pain score≥4 (numeric rating scale [NRS],0-10) at screening and baseline visit. Patients receiving a stable doseof concomitant conventional synthetic disease-modifying antirheumaticdrugs (DMARDs), oral glucocorticoids. NSAIDs and analgesics wereeligible; patients with prior exposure to JAK inhibitors or biologicDMARDs with potential impact on spondyloarthritis were excluded. Of the187 patients randomized to Period 1, 178 (continuous upadacitinib, n=89;placebo switch, n=89) completed week 14 on study drug and entered theopen-label extension; 160 patients (continuous upadacitinib n=78[83.9%]; placebo switch, n=82 [87.2%]) completed week 64. Lack ofefficacy (n=10) and AEs (n=4) were the most common reasons fordiscontinuation of study drug between weeks 14 and 64. In the continuousupadacitinib and the placebo-to-upadacitinib switch groups, meanduration since AS symptom onset was 14.8 and 14.0 years, mean durationsince diagnosis was 7.8 and 6.0 years, mean ASDAS was 3.5 and 3.7, andmean hsCRP levels were 9.6 and 11.4 mg/L, respectively. Concomitantmedications included NSAIDs (76% and 86%), conventional synthetic DMARDs(14% and 18%), and glucocorticoids (6% and 13%, respectively).

Efficacy was assessed based on percentage of patients achieving ASAS20response, ASAS40 response, ASAS partial remission, BASDAI50, andAnkylosing Spondylitis Disease Activity Score (ASDAS) inactive disease(ID; <1.3), low disease activity (LDA; <2.1), major improvement (MI;decrease from baseline≥2.0), and clinically important improvement (CII;decrease from baseline≥1.1) through 64 weeks. In addition, change frombaseline in ASDAS based on C-reactive protein (ASDAS-CRP), BathAnkylosing Spondylitis Functional Index (BASFI), and linear BathAnkylosing Spondylitis Metrology Index (BASMI) through 64 weeks andMaastricht Ankylosing Spondylitis Enthesitis Score (MASES). WorkProductivity and Activity Impairment (WPAI; on a scale of 0-100), ASASHealth Index (HI), and AS quality of life (ASQoL) through 52 wereassessed.

ASAS20 and ASAS40 responses were defined as ≥20% or ≥40% improvement andan absolute improvement of ≥1 or ≥2 units (on an NRS scale of 0-10),respectively, from baseline in ≥3 of the following 4 domains (with noworsening of ≥20% and ≥1 unit or no worsening at all, respectively, inthe remaining domain): Patient Global Assessment of disease activity(PtGA), patient assessment of back pain, BASFI, and inflammation definedas the mean of BASDAI questions 5 and 6 (severity and duration ofmorning stiffness). ASAS partial remission was defined as an absolutescore of ≤2 units for each of the 4 domains identified for ASAS40response. ASDAS-CRP consists of patient-reported outcomes about backpain (BASDAI item 2), peripheral pain/swelling (BASDAI item 3), durationof morning stiffness (BASDAI item 6), the PtGA, and CRP.

The percentage of patients achieving the primary efficacy endpoint ofASAS40 at week 14 continued to increase throughout the study in thecontinuous upadacitinib group: 85% (95% CI, 77%-93%) of patientsachieved ASAS40 at week 64 in the as-observed analysis and 72% (63%-81%)in the NRI analysis (FIG. 12D). An analogous pattern of improvement wasobserved in the ASAS20 (94% [88%-99%] as-observed analysis and 80%[71%-88%] NRI analysis) (FIG. 12E), ASAS partial remission (46%[35%-57%] as-observed analysis and 40% [30%-50%] NRI analysis) (FIG.12F), and BASDAI50 endpoints (82% [74%-91%] as-observed analysis and 70%[61%-79%] NRI analysis) (FIG. 12G). Patients who switched from placeboto upadacitinib at week 14 showed a speed of onset and magnitude ofresponses comparable with patients who were initially randomized toupadacitinib (responses at week 64 were ASAS40: 81% [72%-89%]as-observed analysis and 70% [61%-80%] NRI analysis; ASAS20: 96%[92%-100%] as-observed analysis and 83% [75/6-91%] NRI analysis; ASASpartial remission: 39% [29%-50%] as-observed analysis and 34% [25%-44%]NRI analysis; and BASDAI50: (77% [68%-86%] as-observed analysis and 67%[58%-77%] NRI analysis). Likewise, the percentage of patients achievingASDAS ID (FIG. 12H), ASDAS LDA (FIG. 12I), ASDAS MI (FIG. 12J), andASDAS CII (FIG. 12K) continued to improve throughout the study in thecontinuous upadacitinib group: patients who switched to upadacitinibfrom placebo at week 14 showed a rapid onset of response for thesesendpoints, with responses at week 64 similar to those observed inpatients on continuous upadacitinib.

Mean changes from baseline to 1 year in disease activity (ASDAS),physical function (BASFI), patient assessment of pain and diseaseactivity (PtGA), and inflammation (hsCRP) showed consistent improvementor sustained maintenance throughout the study in the continuousupadacitinib group; a similar magnitude of improvement was seen in theplacebo-to-upadacitinib switch group after initiation of upadacitinib atweek 14. Analogous patterns of improvement were shown in assessments ofquality of life (ASQoL and ASAS HI), spinal mobility (BASMI), andenthesitis (MASES) over time, as well as in measurements of back pain,nocturnal back pain, BASDAI Q2 (back pain) and BASDAI Q5/6. Amongpatients who were employed at baseline, the mean (95% CI) WPAI overallwork impairment score continued to improve throughout the study in thecontinuous upadacitinib group (from −20.5 [−27.1, −14.0] at week 14 to−35.6 [−43.2, −28.0] at week 52; as-observed analysis) andplacebo-to-upadacitinib switch group (from −12.3 [−19.8, −4.8] at week14 to −27.7 [−35.4, −20.0] at week 52).

A significantly higher proportion of patients receiving upadacitinibversus placebo achieved ≥30% and ≥50% reduction in Patient's GlobalAssessment (PGA) of pain and back pain as early as week 2, and ≥70%reduction as early as week 4, and efficacy achieved was sustainedthereafter. See, e.g., FIGS. 12L-12N. Patients who switched from placeboto open-label upadacitinib at week 14 generally reached the same levelof pain reduction after week 14 as those initially randomized toupadacitinib.

Upadacitinib as a Promising Oral Therapy in AS and nr-AxSpA

SELECT-AXIS 1, the first study to report long-term data with a JAKinhibitor in AS, showed that upadacitinib 15 mg QD therapy led tosustained and consistent efficacy up to and including Week 64 in bothNRI and as-observed analyses in patients with active AS who had aninadequate response to NSAIDs. Improvements were seen in diseaseactivity measures (ASDAS, BASDAI, ASAS, and their components),inflammation (hsCRP), physical function (BASFI), quality of life (ASQoL,ASAS HI), and other aspects of disease (BASMI, MASES) with continuousupadacitinib therapy. In patients who switched from placebo toupadacitinib at week 14, a similar speed of onset and magnitude ofefficacy response was observed up to and including Week 64 compared withthose who received continuous upadacitinib starting at Week 0. Of note,approximately 40%-45% of patients receiving upadacitinib reachedremission based on the more difficult to achieve endpoints ASAS partialremission (PR) or ASDAS inactive disease (ID) up to and including Week64, and >80% were in a state of ASDAS low disease activity (LDA).

The below Table 24E provides placebo corrected data for upadacitinib atWeek 14, biologics Ixekizumab and Adalimumab at Week 16, and JAK smallmolecule inhibitors Tofacitinib and Filgotinib at Week 12 for keyprimary and secondary endpoints. While this data is not a head to headcomparison, the placebo corrected response calculated for upadacitinibfor the more difficult to achieve endpoints ASAS PR, ASDAS ID, and ASDASLDA shows decided promise over the efficacy demonstrated by the othertwo JAK small molecule inhibitors, with a remarkable efficacy onlycomparable to that demonstrated with the biologics. Furthermore, thisefficacy, once achieved at Week 14, was sustained or improved overtime,with long term efficacy in these difficult to achieve endpoints(including ASDAS major improvement (MI) and ASDAS clinically importantimprovement (CII)), sustained or improved up to and including Week 64.Coupled with the fact that upadacitinib is well tolerated with no new orunexpected safety findings (particularly compared to the other JAKinhibitors), the data suggests upadacitinib will be a promising new safeoral therapy for AS patients, especially for those AS patients who haveactive disease and inadequate response to NSAIDs.

TABLE 24E Placebo Corrected Responses (4% response/placebo response, pvalue) Ixekiztunab vs. Adalimumab H2H Study ADA 40 mg TofacitinibUpadacitinib Ixekizumab EOW 5 mg BID Filgotinib 15 mg QD Q4W Week 16Week 12 200 mg QD Week 14 Week 16 (TNF (bDMARD- Week 12 Endpoint(naiive) (TNF naiive) naiive) naiive) (Mixed) ASAS20 24.1% 24% 19% 39.6%36.2% (64.5%/40.4% (64%/40%, (59%/40%, (80.8%/41.2%, (75.9%/39.7%, p <0.001) p = 0.0015) p = 0.0075) p ≤ 0.001) p < 0.0001) ASAS40 26.1% 30%18% 26.6% 18.9% (51.6%/25.5% (48%/18%, (36%/18%, (46.2%/19.6%,(37.9%/19%, p < 0.001*) p < 0.0001,) p = 0.0053) p ≤ 0.01) p = 0.0189)BASDAI50 21.8% 25% 15% 18.8% NA (45.2%/23.4%, (42%/17%, (32%/17%,(42.3%/23.5%, p = 0.002*) p = 0.0003) p = 0.0119) p ≤ 0.05) ASAS 18.3%NA NA 7.4% 8.7% Partial (19.4%/1.1%, (19.2%/11.8%, (12.1%/3.4%, Remisson(PR) p < 0.001*) NS) p = 0.1028) ASDAS 16.1% 14% 14% 5.7% 5% InactiveDisease (16.1%/0%, (16%/2%, (16%/2%, (13.5%/7.8%, (5%/0%, (ID) p <0.001) p = 0.0074) p = 0.0087) NS) p = 0.092) ASDAS 38.9% 30% 25% 34.3%NA low disease (49.5%/10.6%, (43%/13%, (38%/13%, (53.9%/19.6%, activity(LDA) p < 0.001) p < 0.0001) p = 0.0002) p ≤ 0.001) NS: non-significant;NA: not available; UPA p values are nominal, unless *significant aftermultiplicity-adjustment; Ixekizumab bDMARD-naïve AS COAST-V Study. Vander Heijde et al. Lancet 2018; 392: 2441-51; Tofacitinib study: van derHeijde D, et al. ARD 2017; 0: 1-8.; Filgotinib study: van der Heijde etal. Lancet 2018; 392: 2378-87.

Example 35: A Phase 3 Protocol in Subjects with Active PsoriaticArthritis and a Previous Inadequate Response to at Least OneNon-Biologic Disease Modifying Anti-Rheumatic Drug (DMARD (SELECT-PSA1)

This is a Phase 3 multicenter study that includes to periods. The StudyDesign for SELECT-PSA1 is provided in FIG. 18. Period 1 is 56 weeks induration and includes a 24-week randomized, double-blind,parallel-group, placebo-controlled and active comparator-controlledperiod followed by an additional 32 weeks of blinded, activecomparator-controlled treatment (Weeks 24-56). Period 1 is designed tocompare the safety, tolerability, and efficacy of upadacitinib free base15 mg QD and 30 mag QD versus placebo and versus adalimumab 40 mg everyother week (eow) in subjects with moderately to severely active PsA andhave an inadequate response to non-biologic DMARDs (DMARD-R). Period isalso designed to compare the efficacy of upadacitinib free base 15 mg QDand 30 mg QD versus placebo for the prevention of structuralprogression. Period 2 is an open-label (blinded until the last subjectcompletes the last visit of Period 1), long-term extension of up to atotal treatment duration of approximately 3 years to evaluate thesafety, tolerability and efficacy of upadacitinib free base 15 mg QD and30 mg QD in subjects with moderately to severely active PsA who havecompleted Period 1, 15 rag or 30 rag upadacitinib refers to the 15 ragand 30 mg once-daily (QD) upadacitinib drug product as described hereinbelow (Table 25A). Table 25A. Upadacitinib 15 and 30 mg Extended Release(ER) Tablets (Wet Granulated)

TABLE 25A Upadacitinin 15 and 30 mg Extended Release (ER) Tablets (WetGranulated) Component Function 15 mg 30 mg Tablet Core IntragranularUpadacitinib* Drug substance 15.4 30.7 Microcrystalline cellulose Filler41.2 82.4 (≥65% through 75 um screen) (Avicel PH 102) Hypromellose 2208Control release 4.9 9.8 polymer and binder Purified water Wetting agentN/A N/A Extragranular Microcrystalline cellulose Filler 121.3 64.8 (≥65%through 75 um screen) (Avicel PH 102) Mannitol (Pearlitol 100 SD) Filler100.6 100.6 Tartaric acid powder pH modifier 96.0 96.0 Hypromellose 2208Control release 91.1 86.2 polymer Colloidal Silicon Dioxide Glidant 2.42.4 Magnesium Stearate Lubricant 7.2 7.2 Film Coat OPADRY II Yellow(PVA, TiO₂, Film coat 14.40 14.40 PEG-3350, Talc, Iron Oxide Yellow)Purified water** Processing Aid N/A N/A *hemihydrate upadacitinib freebase Form C as disclosed in WO2017066775 and WO 2018/165581 is used, 15mg and 30 mg amount per tablet refers to the amount of anhydrousupadacitinib free base in the tablet; **removed during processing,

The study duration includes a 35-day screening period; a 56-week blindedperiod which includes 24 weeks of double-blind, placebo-controlled andactive comparator controlled treatment followed by 32 weeks of activecomparator controlled treatment (Period 1); a long-term extension periodof up to a total treatment duration of approximately 3 years ([blindeduntil the last subject completes the last visit of Period 1] Period 2),a 30-day follow-up call or visit; and a 70-day follow-up call.

Subjects who met eligibility criteria were stratified by extent ofpsoriasis (≥3% body surface area [BSA] or <3% BSA), current use of atleast 1 DMARD, presence of dactylitis, and presence of enthesitis,except for subjects from China and Japan, where randomization for eachcountry was stratified by extent of psoriasis (≥3% body surface area[BSA] or <3% BSA) only, and then randomized in a 2:2:2:1:1 ratio to oneof five treatment groups:

-   -   Group 1: upadacitinib 15 mg QD (N=430)    -   Group 2: upadacitinib free base 30 mg QD (N=423)    -   Group 3: adalimumab (ADA) (40 mg eow) (N=429)    -   Group 4: Placebo followed by upadacitinib free base 15 mg QD        (N=211)    -   Group 5: Placebo followed by upadacitinib free base 30 mg QD        (N=212)

No more than approximately 15% of subjects were enrolled withconcomitant use of hydroxychloroquine, sulfasalazine, bucillamine, origuratimod.

Subjects received both oral study drug QD (upadacitinib free base 15 mg,upadacitinib free base 30 mg, or matching placebo) and subcutaneousstudy drug cow (either ADA 40 mg or matching placebo) until all subjectscompleted Period 1 (Week 56) and sites and subjects are unblinded tostudy treatment.

Subjects who were assigned to placebo at Baseline were preassigned toreceiving either upadacitinib free base 15 mg QD or upadacitinib freebase 30 mg QD starting at Week 24 in a 1:1 ratio. Subjects who completethe Week 56 visit (end of Period 1) will enter the long-term extensionportion of the study. Period 2 (total study duration up to approximately3 years). Subjects will continue study treatment as assigned inPeriod 1. Subjects who are assigned to the upadacitinib free base 15 mgQD, upadacitinib free base 30 mg QD, or adalimumab 40 mg eow willcontinue to receive upadacitinib free base 15 mg QD, upadacitinib freebase 30 mg QD, or adalimumab 40 mg cow, respectively, in a blindedmanner. When the last subject completes the last visit of Period 1 (Week56), study drug assignment in both periods will be unblinded to thesites, and subjects will be dispensed study drug in an open-labelfashion until the completion of Period 2.

Subjects must have had inadequate response to ≥1 non-biologic DMARD(MTX, SSZ, LEF, apremilast, bucillamine or iguratimod) or an intoleranceto or contraindication for DMARDs prior to the Screening visit. Nobackground non-biologic DMARD therapy is required during participationin this study. For subjects who are on non-biologic DMARD therapy atbaseline (MTX, SSZ. LEF, apremilast, hydroxychloroquine (HCQ),bucillamine or iguratimod), non-biologic DMARDs should have been started≥12 weeks prior to the baseline visit, must be at stable dose for ≥4weeks prior to the first dose of study drug and remain on a stable dosethrough Week 36 of the study: the non-biologic DMARD dose may bedecreased only for safety reasons. In addition, all subjects taking MTXshould take a dietary supplement of oral folic acid (or equivalent)throughout study participation.

At Week 16, rescue therapy will be offered to subjects classified asnon-responders (defined as not achieving at least 20% improvement ineither or both tender joint count (TJC) and swollen joint count (SJC) atboth Week 12 and Week 16) as follows: 1) add or modify doses ofnon-biologic DMARDs, NSAIDs, acetaminophen/paracetamol, low potencyopioid medications (tramadol or combination of acetaminophen and codeineor hydrocodone), oral corticosteroids and/or 2) receive 1intra-articular, trigger point or tender point, intra-bursa, orintra-tendon sheath corticosteroid injection for 1 peripheral joint, 1trigger point, 1 tender point, 1 bursa, or 1 enthesis (Rescue Therapy).

After the last subject completes the Week 24 study visit, an unblindedanalysis will be conducted for the purpose of initial regulatorysubmission. To maintain integrity of the trial during the blinded56-week period, study sites and subjects will remain blinded until allsubjects have reached Week 56. A second unblinded analysis may beconducted for regulatory purposes after all subjects have completedPeriod 1. A final analysis will be conducted after all subjects havecompleted Period 2.

Primary and Secondary Endpoints

The primary efficacy endpoint is the proportion of subjects achievingAmerican College of Rheumatology (ACR) 20% response rate at Week 12. Theprimary and secondary clinical endpoints for this study (SELECT-PSA1clinical study; Example 35) and the SELECT-PSA2 clinical study (Example36) are further described in Example 37.

Study Population

Patients with active psoriatic arthritis and a previous inadequateresponse to at least one non-biologic disease-modifying anti-rheumaticdrug (non-biologic DMARD or DMARD).

Main Inclusion criteria include:

-   1. Adult male or female, ≥18 years old at Screening.-   2. Clinical diagnosis of PsA with symptom onset at least 6 months    prior to the Screening Visit and fulfillment of the Classification    Criteria for PsA (CASPAR) criteria.-   3. Subject has active disease at Baseline defined as ≥3 tender    joints (based on 68 joint counts) and ≥3 swollen joints (based on 66    joint counts) at Screening and Baseline Visits.-   4. Presence of either at Screening:    -   ≥1 erosion on x-ray as determined by central imaging review or;    -   hs-CRP>laboratory defined upper limit of normal (ULN).-   5. Diagnosis of active plaque psoriasis or documented history of    plaque psoriasis.-   6. Subject has had an inadequate response (lack of efficacy after a    minimum 12 week duration of therapy) to previous or current    treatment with at least 1 non-biologic DMARD at maximally tolerated    dose or up to dose defined in Inclusion Criterion 7 [(inadequate    response to MTX is defined as ≥15 to ≤25 mg/week; or ≥10 mg/week in    subjects who are intolerant of MTX at doses≥12.5 mg/week after    complete titration; for subjects in China. Taiwan, and Japan    inadequate response to MTX is defined as ≥7.5 mg/week), SSZ, LEF,    cyclosporine, apremilast, bucillamine or iguratimod)], or subject    has an intolerance to or contraindication for DMARDs.-   7. Subject who is on current treatment with concomitant non-biologic    DMARDs at study entry must be on ≤2 non-biologic DMARDs (except the    combination of MTX and leflunomide) at the following doses: MTX (≤25    mg/week). SSZ (≤3000 mg/day), leflunomide (LEF) (≤20 mg/day),    apremilast (≤60 mg/day), HCQ (≤400 mg/day), bucillamine (≤300    mg/day) or iguratimod (≤50 mg/day) for ≥12 weeks and at stable dose    for ≥4 weeks prior to the Baseline Visit. No other DMARDs are    permitted during the study. Subjects who need to discontinue DMARDs    prior to the Baseline Visit to comply with this inclusion criterion    must follow the procedure specified below or at least five times the    mean terminal elimination half-life of a drug:    -   ≥8 weeks for LEF if no elimination procedure was followed, or        adhere to an elimination procedure (i.e., 11 days with        cholestyramine, or 30-day washout with activated charcoal or as        per local label);    -   ≥4 weeks for all others-   8. Stable doses of non-steroidal anti-inflammatory drugs (NSAIDs),    acetaminophen/paracetamol, low-potency opiates (tramadol or    combination of acetaminophen and codeine or hydrocodone), oral    corticosteroids (equivalent to prednisone≤10 mg/day), or inhaled    corticosteroids for stable medical conditions are allowed, but must    have been at a stable dose for ≥1 week prior to the Baseline Visit.-   9. Subjects must have discontinued all opiates (except for tramadol,    or combination of acetaminophen and codeine or hydrocodone) at least    1 week and oral traditional Chinese medicine for at least 4 weeks    prior to the first dose of study drug.-   10. Where mandated by local requirements only, treatment with at    least one of the following background medications is required:    non-biologic DMARDs, NSAIDs, acetaminophen, low potency opiates    (tramadol or combination of acetaminophen codeine or hydrocodone),    or oral corticosteroids at doses.

Main Exclusion Criteria Include:

-   1. Prior exposure to any Janus Kinase (JAK) inhibitor (including but    not limited to ruxolitinib, tofacitinib, baricitinib, and    filgotinib).-   2. Current treatment with >2 non-biologic DMARDs or use of DMARDs    other than MTX, SSZ, LEF, apremilast, HCQ, bucillamine or iguratimod    or use of MTX in combination with LEF at Baseline.-   3. History of fibromyalgia, any arthritis with onset prior to age 17    years, or current diagnosis of inflammatory joint disease other than    PsA (including, but not limited to rheumatoid arthritis, gout,    overlap connective tissue diseases, scleroderma, polymyositis,    dermatomyositis, systemic lupus erythermatosus). Prior history of    reactive arthritis or axial spondyloarthritis including ankylosing    spondylitis and non-radiographic axial spondyloarthritis is    permitted if documentation of change in diagnosis to PsA or    additional diagnosis of PsA is made. Prior history of fibromyalgia    is permitted if documentation of change in diagnosis to PsA or    documentation that the diagnosis of fibromyalgia was made    incorrectly.

Analysis Windows

The following rules will be applied to assign actual subject visits toprotocol-specified visits. For each protocol-specified study visit, atarget study day will be identified to represent the corresponding visitalong with a window around the target day. Windows will be selected in anon-overlapping fashion so that a collection date does not fall intomultiple visit windows. If a subject has two or more actual visits inone visit window, the visit closest to the target day will be used foranalysis. If two visits are equidistant from the target day, then thelater visit will be used for analysis.

Results Up to and Including Week 24

As noted above, after the last subject completed the Week 24 studyvisit, an unblinded analysis was conducted for the purpose of initialregulatory submission.

The study met the primary endpoint ACR20 at Week 12. At week 12, theprimary outcome of ACR20 response was achieved by 153 (36.2%) patientsreceiving placebo versus 303 (70.6%; difference: 34.5%; 95% CI: 28.2 to40.7; P<0.001) receiving upadacitinib 15 mg and 332 (78.5%; difference:42.3%; 95% CI: 36.3 to 48.3; P<0.001) receiving upadacitinib 30 mg; 279(65.0%) patients receiving adalimumab achieved ACR20 response ratesversus upadacitinib 15 mg (difference: 5.6%; 95% CI: −0.6 to 11.8) and30 mg (difference: 13.5%; 95% CI: 7.5 to 19.4; P<0.001. Upadacitinib 30mg was superior to adalimumab; the 15 mg dose was not superior toadalimumab, which prevented the testing of significance for secondaryendpoints lower in the testing hierarchy. The efficacy of upadacitinibfreebase 15 mg was demonstrated regardless of subgroups evaluatedincluding baseline BMI, baseline hsCRP, and number of prior non-biologicDMARDs (≤1 or >1).

The study also showed statistical significance for the non-inferiority(NI) of ACR20 at Week 12 compared to adalimumab for both upadacitinibfree base doses. After achieving the non-inferiority (NI) comparisons,superiority tests compared to adalimumab were conducted. Upadacitinibfree base 30 mg showed superiority vs. adalimumab in ACR20 at Week 12.

The results for key secondary endpoints versus placebo were consistentwith that of the primary endpoint. At week 12, treatment differences(95% CI) in ACR50 response versus placebo for upadacitinib 15 mg and 30mg were 24.3% (18.7 to 29.9) and 38.5% (32.8 to 44.3), respectively andversus adalimumab were 0.0% (−6.5 to 6.5) and 14.2% (7.6 to 20.9),respectively. Treatment differences (95% CI) in ACR70 response versusplacebo for upadacitinib 15 mg and 30 mg were 13.3% (9.5 to 17.0) and22.9% (18.5 to 27.3), respectively and versus adalimumab were 1.9/6(−2.9 to 6.6) and 11.5% (6.3 to 16.8), respectively. At week 24, thepercentage of patients achieving ACR20/50/70 responses were in the samedirection as the primary endpoint for both upadacitinib doses versusplacebo and adalimumab; no clinical inferences can be drawn from thesedata. At week 24, the percentage of patients achieving Minimal DiseaseActivity (MDA) was significantly greater with both upadacitinib dosesversus placebo (P<0.001 for both comparisons) and was in the samedirection as the primary outcome versus adalimumab.

At week 16, a significantly greater percentage of patients achievedPsoriasis Area Severity Index of at least 75% (PASI 75) and StaticInvestigator Global Assessment of Psoriasis of 0 or 1 and at least a2-point improvement from baseline (sIGA 0/1) response with bothupadacitinib doses versus placebo (P<0.001 for each comparison). Thepercentage of patients achieving PASI 75 response was in the samedirection as the primary endpoint for both upadacitinib doses versusadalimumab, and for sIGA 0/1 response with upadacitinib 30 mg: thepercentage of sIGA 0/1 responders was not significantly different forupadacitinib 15 mg versus adalimumab. Greater improvement inpatient-reported psoriasis symptoms, as measured by the Self-Assessmentof Psoriasis Symptoms (SAPS), was also observed at Week 16 in patientstreated with upadacitinib freebase 15 mg QD compared to placebo.Statistically greater efficacy was observed with each upadacitinib doseversus placebo for change from baseline in HAQ-DI, SF-36 PCS, andFACIT-F at week 12 (P<0.001 for each comparison). The proportion ofHAQ-DI responders (≥0.35 improvement from baseline in HAQ-DI score) atWeek 12 was 58% in patients receiving upadacitinib freebase 15 mg QD and33% in patients receiving placebo.

Health-related quality of life was assessed by SF-36. Patients receivingupadacitinib freebase 15 mg QD experienced significantly greaterimprovement from baseline in the Physical Component Summary scorecompared to placebo at Week 12. Greater improvement was also observed inthe Mental Component Summary score and all 8 domains of SF-36 (PhysicalFunctioning, Bodily Pain, Vitality. Social Functioning, Role Physical.General Health, Role Emotional, and Mental Health) compared to placebo.

At week 24, significantly more upadacitinib-treated patients achievedresolution of enthesitis versus placebo (P<0.001 for each comparison);upadacitinib 15 mg was not significantly different to adalimumab forresolution of enthesitis and results with upadacitinib 30 mg were in thesame direction as the primary endpoint. Rates for resolution ofdactylitis are presented in the below Tables. The study alsodemonstrated significantly greater efficacy in PsA signs and symptoms aswell as inhibition of radiographic progression compared to placebo. Forexample, at week 24, upadacitinib-treated patients exhibitedsignificantly less radiographic progression versus placebo-treatedpatients as demonstrated by the change from baseline in modified totalSharp/van der Heijde Score (mTSS; P<0.001) (mTSS equivalent to SHS);mean progression was not different for upadacitinib and adalimumab.Statistically significant results were also achieved for both erosionand joint space narrowing scores for the 15 mg QD dosage. The proportionof patients with no radiographic progression (mTSS change≤0) was higherwith upadacitinib freebase 15 mg QD (93%) compared to placebo (89/6) atWeek 24. These results are summarized below in the below Tables.

A summary of primary and key secondary efficacy results are presented inthe below Tables (Parts 1 and 2). See also FIGS. 19A-19B for a listingof the ranked secondary endpoints. Parts 1 and 2. The time course of theACR20 response and associated 95% confidence interval (CI) up to andincluding Week 24 is presented in FIG. 20A, and results for additionalkey secondary endpoints are presented in FIGS. 20B20BB. It was observedthat this clinical efficacy achieved was sustained with continued dailydosing.

TABLE 25B Demographics and Characteristics at Baseline UpadacitinibUpadacitinib Adalimumab Placebo 15 mg QD 30 mg QD 40 mg EOW N = 423 N =429 N = 423 N = 429 Female, n (%) 211 (49.9) 238 (55.5) 236 (55.8) 222(51,7) Age (years) 50.4 ± 12.2 51.6 ± 12.2 49.9 ± 12.4 51.4 ± 12.0 Whiterace, n (%) 377 (89.1) 386 (90.0) 377 (89.1) 375 (87.4) BMI ≥25 kg/m², n(%) 329 (77.8) 342 (79.7) 319 (75.4) 334 (77.9) Duration since PsAdiagnosis (years)  6.2 ± 7.0  6.2 ± 7.4  5.9 ± 6.4  5.9 ± 7.1 Anynon-biologic DMARD at baseline, 347 (82.0) 353 (82.3) 346 (81.8) 347(80,9) n (%) MTX alone 267 (63.1) 279 (65) 268 (63.4) 270 (62.9) MTX +another non-biologic  26 (6.1)  20 (4.7)  27 (6.4)  16 (3.7) DMARDNon-biologic DMARD other than  54 (12.8)  54 (12.6)  51 (12.1)  61(14.2) MTX Glucocorticoid use at baseline, n (%)  70 (16.5)  73 (17.0) 71 (16.8)  72 (16.8) TJC68 20.4 ± 14.3 20.4 ± 14.7 19.4 ± 13.3 20.1 ±13.8 SJC66 11.0 ± 8.2 11.6 ± 9.3 10.6 ± 7.1 11.6 ± 8.8 hs-CRP > ULN^(a), n (%) 324 (76.6) 324 (75.5) 324 (76.6) 308 (71.8) HAQ-DI 1.12 ±0.6 1.15 ± 0.7 1.09 ± 0.6 1.12 ± 0.6 Patient's Assessment of Pain  6.1 ±2.1  6.7 ± 2.1  5.9 ± 2.1  6.0 ± 2.1 (NRS 0-10) BSA-psoriasis ≥3%, n (%)211 (49.9) 214 (49.9) 210 (49.6) 211 (49.2) PASI (for baselineBSA-psoriasis ≥3%) 11.2 ± 11.4 9.78 ± 10.0  9.5 ± 8.8  9.4 ± 8.5 sIGA ofPsoriasis score, n (%) 0  24 (5.7)  34 (7.9)  21 (5.0)  34 (7.9) 1  86(20.3)  73 (17.0)  78 (18.4)  65 (15.2) 2 167 (39.5) 170 (39.6) 173(40.9) 181 (42.2) 3 119 (28.1) 133 (31.0) 128 (30.3) 132 (30.8) 4  27(6.4)  19 (4.4)  23 (5.4)  17 (4.0) Presence of enthesitis 241 (57.0)270 (62.9) 267 (63.1) 265 (61.8) (defined as LET >0), n (%) Presence ofdactylitis 126 (29.8) 136 (31.7) 127 (30.0) 127 (29.6) (defined asLDI >0), n (%) Values are mean ± SD unless noted. ^(a)ULN >2.87 mg/L;Permitted concomitant non-biologic DMARDs included: methotrexate,sulfasalazine, leflunomide, apremilast, hydroxychloroquine, bucillamine,and iguratimod. BMI, body mass index; BSA, body surface area; DMARD,disease-modifying anti-rheumatic drug; EOW, every other week; HAQ-DI,Health Assessment Questionnaire-Disability Index; hs-CRP,high-sensitivity C-reactive protein; LDI, Leeds Dactylitis Index; LEI,Leeds Enthesitis Index; MTX, methotrexate; NRS, numeric rating scale;NSAID, nortsteroidal anti-inflammatory drug; PASI, psoriasis areaseverity index; PsA, psoriatic arthritis; QD, once daily; SD, standarddeviation; ULN, upper limit normal; SD, standard deviation; sIGA, StaticInvestigator Global Assessment of Psoriasis; SIC, swollen joint count;TIC, tender joint count.

TABLE 25C Primary and Ranked Secondary Efficacy Endpoints-Part 1 ADA UPAUPA Summary Statistics PLACEBO 40 MG EOW 15 MG QD 30 MG QD % or LS Mean(P-Value) Endpoint^(a) N = 423 N = 429 N = 429 N = 423 Primary ACR2036.2% 65.0% 70.6% 78.5% (Wk12) (<0.0001*) (<0.0001*) Ranked 1 HAQ-DI−0.14 −0.34 −0.42 −0.47 Secondary (Wk12) (<0.0001*) (<0.0001) Endpoints2 sIGA 10.9% 38.5% 41.9% 54.0% (Part 1) (Wk16)^(b) (<0.0001 *)(<0.0001*) 3 PASI 75 21.3% 53.1% 62.6% 62.4% (Wk16)^(c) (<0.0001*)(<0.0001*) 4 SHS 0.25 0.01 −0.04 0.03 (mTSS) (0.0002*) (0.0069*) (Wk24)5 MDA 12.3% 33.3% 36.6% 45.4% (Wk24) (<0.0001) (<0.0001) 6 Enthesitis53.7% 57.7% Resolution 32.4% 47.2% (<0.0001*) (<0.0001*) (Wk 24)^(d) 7ACR 20 36.2% 65.0% 70.6% 78.5% NI vs (<0.0001*) (<0.0001*) ADA^(e)(Wk12) 8 SF-36 3.19 6.82 7.86 8.90 PCS (<0.0001*) (<0.0001*) (Wk12) 9FACIT-F 2.8 5.7 6.3 7.1 (Wk12) (<0.0001*) (<0.0001*) Note: The nominalp-values are provided in parentheses. *Achieved statistical significanceusing graphical multiple testing procedure controlling the overall typeI error rate at 2-sided 0.0499 level. Note that 0.0001 was spent at theinterim futility analysis. ^(a)Results for binary endpoints are based onNRI analysis. Results for MDA and enthesitis resolution at week 24 arebased on non-responder imputation with additional rescue handling, wheresubjects rescued at Week 16 are imputed as non-responders. Results forcontinuous endpoints are based on MMRM model with fixed effects oftreatment, visit, treatment-by-visit interaction, the stratificationfactor of current DMARD use (yes/no) and baseline measurement. Resultsfor SHS are based on ANCOVA with linear extrapolation for missing dataand rescue handling. ^(b)Summarized for subjects with baseline sIGA ≥ 2;N_((pbo)) = 313, N_((ADA)) = 330, N_((upa15)) = 322, N_((upa30)) = 324.^(c)Summarized for subjects with baseline BSA affected by psoriasis ≥3%; N(pbo) = 211, N(ADA) = 211, N(upa15) = 214, N(upa30) = 210.^(d)Summaried for subjects with baseline LEI > 0; N(pbo) = 241, N(ADA) =265, N(upa15) = 270, N(upa30) = 267. ^(e)Non-inferiority test ofupadacitinib vs adalimumab, perserving 50% of adlimumab effect.

TABLE 25D Ranked Secondary Efficacy Endpoints in Part 2 and Other KeySecondary Endpoints ADA UPA UPA Summary Statistics PLACEBO 40 MG EOW 15MG QD 30 MG QD % or LS Mean (P-Value) Endpoint^(a) N = 423 N = 429 N =429 N = 423 Ranked 10 ACR 20 36.2% 65.0% 70.6% 78.5% Secondary Sup. vs(0.0815) (<0.0001) Endpoints ADA^(b) (Part 2) (Wk12) 11 Dactylitis 39.7%74.0% 76.5% 79.5% Resolution (<0.0001) (<0.0001) (Wk24)^(c) 12 Pain −0.9−2.3 −2.3 −2.7 Sup. vs (0.8970) (0.0028) ADA^(b) (Wk12) 13 HAQ-D1 −0.14−0.34 −0.42 −0.47 Sup. vs (0.0162) (<0.0001) ADA^(b) (Wk12) 14 SAPS −8.2−22.7 −25.3 −28.1 (Wk16) (<0.0001) (<0.0001) Other Key ACR50 13.2% 37.5%37.5% 51.8% Secondary (Wk12) (<0.0001) (<0.0001) ACR70  2.4% 13.8% 15.6%25.3% (Wk12) (<0.0001) (<0.0001) ACR20 12.1% 30.3% 28.2% 38.3% (Wk2)(<0.0001) (<0.0001) Note: The nominal p-values are provided inparentheses. *Statistical significance using graphical multiple testingprocedure controlling overall type I error rate. ^(a)Results for binaryendpoints are based on NRI analysis. Results for dactylitis resolutionat week 24 is based on non-responder imputation with additional rescuehandling, where subjects rescued at Week 16 are imputed asnon-responders. Results for continuous endpoints are based on MMRM modelwith fixed effects of treatment, visit, treatment-by-visit interaction,the stratification factor of current DMARD use (yes/no) and baselinemeasurement. ^(b)Superiority test of upadacitinib vs. adalimumab.^(c)Summarized for subjects with baseline LDI > 0; N(pbo) = 126, N(ADA)= 127, N(upa15) = 136, N(upa30) = 127.

TABLE 25E Additional Efficacy Endpoints for SELECT-PSA1: Summarized forsubjects with baseline BSA affected by psoriasis ≥3%^(a) ADA CPA UPAPLACEBO 40 MG EOW 15 MG QD 30 MG QD Endpoint N = 211 N = 211 N = 214 N =210 PASI 90 12.3% 38.9% 38.3% 49.5% (Wk 16) (<0.0001) (<0.0001) PASI 100 7.1% 19.9% 23.8% 33.8% (Wk 16) (<0.0001) ^(a)Fall analysis set: N(placebo) = 423, N(ADA) = 429, N(UPA15) = 429, N(UPA30) = 423.

Additional data for ACR20, ACR50, and ACR70 response at Week 24, andMDA, resolution of enthesitis (LEI=0), and resolution of dactylitis(LDI=0) at week 12 is set forth in the below Table 25F.

TABLE 25F Additional Clinical Responses Placebo CPA (N = 423) 15 mg QDEndpoint % (N = 429) ACR20 (Wk 24) 45 73 ACR50 (Wk 24) 19 52 ACR70 (Wk24) 5 29 MDA (Wk 12) 6 25 Enthesitis resolution^(a) 33 47 (Wk 12)Dactylitis resolution^(b) 42 74 (Wk 12) Patients who discontinuedrandomized treatment or were missing data at week of evaluation wereimputed as non-responders in the analyses. For MDA, resolution ofenthesitis; and resolution of dactylitis at Week 24, the subjectsrescued at Week 16 were imputed as non-responders in the analyses.^(a)In patients with enthesitis at baseline (n = 241 and 270,respectively) ^(b)In patients with dactylitis at baseline (n = 126 and136)

Treatment with upadacitinib freebase 15 mg resulted in improvements inindividual ACR components, including tender/painful and swollen jointcounts, patient and physician global assessments of disease activity,HAQ-DI, pain assessment, and hsCRP compared to placebo. These resultsare shown in FIGS. 20F-20K and 20Q. Onset of efficacy was seen as earlyas Week 2 for ACR20 and its components.

Inhibition of progression of structural damage was assessedradiographically and expressed as the change from baseline in modifiedTotal Sharp Score (mTSS) and its components, the erosion score and thejoint space narrowing score, at Week 24. Treatment with upadacitinibfreebase 15 mg QD resulted in significantly greater inhibition of theprogression of structural joint damage compared to placebo at Week 24.Statistically significant results were also achieved for both erosionand joint space narrowing scores. The proportion of patients with noradiographic progression (mTSS change≤0) was higher with upadacitinibfreebase 15 mg QD (93%) compared to placebo (89%) at Week 24. Theseresults are summarized in FIG. 20Z.

The safety profile of upadacitinib in this trial was generally similarto the safety profile observed in other upadacitinib clinical trials.Through week 24, the rates of treatment-emergent adverse events andserious adverse events, including serious infections, were similar withplacebo, adalimumab, and upadacitinib 15 mg but higher with upadacitinib30 mg. The most common AE was upper respiratory tract infection. Ratesof serious infections were 0.9%, 0.7%, 1.2%, and 2.6% with placebo,adalimumab, upadacitinib 15 mg and 30 mg, respectively. Up to week 24,treatment-emergent opportunistic infections included one event ofCandida urethritis with upadacitinib 15 mg, and one event each ofpneumocystis jirovecii pneumonia and cytomegalovirus with upadacitinib30 mg. There were 3, 4, and 5 cases of herpes zoster reported withplacebo and upadacitinib 15 mg and 30 mg, respectively. One malignancyoccurred in each of the placebo and upadacitinib 15 mg arms, and 3malignancies were reported in each of the upadacitinib 30 mg andadalimumab arms. No major adverse cardiovascular events (MACE) werereported with upadacitinib. One event of deep vein thrombosis wasreported with placebo and 2 events with adalimumab: one event ofpulmonary embolism was reported with upadacitinib 30 mg. One death,adjudicated to unknown cause, was reported with placebo.

Mean hemoglobin, neutrophil, lymphocyte, and platelet levels remainedwithin normal limits from baseline through week 24 in all treatmentarms. Adverse events of anemia and lymphopenia were reported at similarrates for upadacitinib 15 mg and placebo and more often withupadacitinib 30 mg. Adverse events of neutropenia were more common withupadacitinib compared to placebo. Overall, the frequency of Grade≥3laboratory abnormalities was ≤2.1%; most resolved without interruptionin therapy. No patients had Grade 4 decreases in hematology parameters.One patient each reported isolated Grade 3 decrease in hemoglobin orplatelets after discontinuation with upadacitinib 30 mg. The frequencyof Grade 3 neutrophil and lymphocytes decreases was higher forupadacitinib 30 mg compared to other arms.

Hepatic disorder adverse events were reported in 3.8%, 15.6%, 9.1%, and12.3% of the placebo, adalimumab, upadacitinib 15 mg and 30 mg groups,respectively. Most alanine aminotransferase (ALT) or aspartateaminotransferase (AST) increases were mild to moderate (Grade 2 orless). Grade 3 elevations in ALT occurred in 1.7%, 0.9%, 0.9%, and 1.2%with placebo, adalimumab, upadacitinib 15 mg and 30 mg, respectively.Grade 3 elevations in AST occurred in 0.5%, 0.2%, 0%, and 0.7% withplacebo, adalimumab, and upadacitinib 15 mg and 30 mg, respectively. NoGrade 4 elevations in ALT values were reported; 1 patient in theupadacitinib 30 mg group had a Grade 4 increase in AST at a single timepoint. No Hy's law cases were reported. Grade 3 or 4 increases increatine phosphokinase (CPK) values were more common with upadacitiniband were reported in <2% of patients; no patients experiencedrhabdomyolysis.

Mean increases in low-density lipoprotein cholesterol (LDL-C) andhigh-density lipoprotein cholesterol (HDL-C) were observed withupadacitinib in comparison to placebo. LDL-C:HDL-C and totalcholesterol:HDL-C ratios did not change through week 24.

Upadacitinib as a Promising Oral Therapy for the Treatment of PsA

A review of the placebo corrected data for upadacitinib and the JAKsmall molecule inhibitor Tofacitinib (approved for the lower (5 mg BID)dose in the treatment of PsA) for key primary and secondary endpoints,while not a head to head comparison, suggests that upadacitinib 13 mg QDand 30 mg QD shows decided promise for the more difficult to achieveendpoints of minimal disease activity (MDA), as well as psoriasisendpoints PASI 75 or PASI 90, as well as certain ACR components (e.g.,ACR20/50/70). It was observed that this clinical efficacy achieved wassustained with continued daily dosing (Table 25G).

TABLE 25G Placebo Corrected Responses (% response/placebo response)Upadacitinib H2H Adalimumab Tofacitinib Select PsA1 Opal Ixekizumamb Upa15 Upa 30 Broaden Spirit P1 mg QD mg QD Tofa 5 mg Tofa 10 IXE 80 mg IXE80 Week Week Adalimumab BID mg BID Q4W mg Q2W Endpoint 12/16/24 12/16/24Week 12/24 Week 12 Week 12 Week 24 Week 24 ACR20 Week 12 Week 12 Week 1217% 28% 28% 32% 34% 42% 29% (50%/ (61%/ (57.9%/ (62.1%/ (70.6%/36.2%,(78.5%/36.2%, (65%/36.2%) 33%, 33%, 30.2%, 30.2%, p ≤ 0.001) p ≤ 0.001)p ≤ 0.05) p ≤ 0.001) p ≤ 0.001) p ≤ 0.001) ACR50 Week 12 Week 12 Week 1218% 30% 25% 32% 24% 39% 24% (28%/10%, (40%/10%, (40.2%/15.1%,(46.6%/15.1,% (37.5%/13.2%, (51.8%/13.2%, (37.5%/13.2%) p ≤ 0.001) p ≤0.001) p ≤ 0.001) p ≤ 0.001) p ≤ 0.001) p ≤ 0.001) ACR70 Week 12 Week 12Week 12 12% 9% 18% 28% 13% 23% 11.4% (17%/5%, (14%/5%, (23.4%/5.7%,(34.0%/5.7%, (15.6%/2.4%, (25.3%/2.4%, (13.8%/2.4%) p ≤ 0.01) p ≤ 0.05)p ≤ 0.001) p ≤ 0.001) p ≤ 0.001) p ≤ 0.001) MDA Week 24 Week 24 Week 2419% 18% 15% 26% 24% 33% 21% (26%/7%) (25%/7%) (29.9%/15.1%,(40.8%/15.1%, (36.6%/12.3%, (45.4%/12.3%, (33.3%/ p ≤ 0.01 p ≤ 0.01) p ≤0.001) p ≤ 0.001) 12.3%) PASI 75 Week 16 Week 16 Week 16 28% 29% 61% 69%41% 41% 31.8% (43%/15%, (44%/15%, (71.2 %/10.4%, (79.9%/10.4%,(62.6%/21.3%, (62.4%/21.3%, (53.1%/21.3%) p ≤ 0.001) p ≤ 0.001) p ≤0.001) p ≤ 0.001) p ≤ 0.001) p ≤ 0.001) PASI 90 Week 16 Week 16 Week 1617% 27% 50% 52% 26% 37% 17.6% (27%/7%, (27%/7%, (56.2%/6%, (67.8%/6%,(38.3%/12.3%, (49.5%/12.3%, (38.9%/21.3%) p ≤ 0.01) p ≤ 0.001) p ≤0.001) p ≤ 0.001) p ≤ 0.001) p ≤ 0.001) Tofacitinib study: Mease P etal. N Engl J Med 2017; 377: 1537-1550 (5 mg BID dose is approved in theUnited States for treatment of PsA; 10 mg BID dose is not approved inthe United States); Ixekizumab study: Mease PJ et al. Ann Rheum Dis2017; 76: 79-87.

Example 36: A Phase 3 Protocol in Subjects with Active PsoriaticArthritis and a Previous Inadequate Response to at Least One BiologicDisease Modifying Anti-Rheumatic Drug (bDMARD) (SELECT PSA2)

This is a Phase 3 multicenter study that includes two periods. The Phase3 Study Design for SELECT-PSA2 is provided in FIG. 21. Period 1 is 56weeks in duration and includes a 24-week randomized, double-blind,parallel-group, placebo-controlled period followed by an additional 32weeks of blinded treatment (Weeks 24-56). Period 1 is designed tocompare the safety, tolerability, and efficacy of upadacitinib free base15 mg QD and 30 mg QD versus placebo in subjects with moderately toseverely active PsA who have an inadequate response to at least oneBiological Disease Modifying Anti-Rheumatic Drug (bDMARD) (PsA Bio-IR).Period 2 is an open label (blinded until the last subject completes thelast visit of Period 1) long-term extension of up to a total treatmentduration of approximately 3 years to evaluate the safety, tolerabilityand efficacy of upadacitinib free base 15 mg QD, and 30 mg QD, insubjects with PsA who have completed Period 1. 15 mg or 30 mgupadacitinib refers to the 15 mg and 30 mg once-daily (QD) upadacitinibdrug product as described in Example 35.

The study duration includes a 35-day screening period; a 56-week blindedperiod which includes 24 weeks of double-blind, placebo-controlledtreatment followed by 32 weeks of treatment blinded to dose ofupadacitinib (Period 1): a long-term extension period of up to a totaltreatment duration of approximately 3 years ([blinded until the lastsubject completes the last visit of Period 1] Period 2); and a 30-dayfollow-up call or visit.

Subjects who met eligibility criteria were stratified by extent ofpsoriasis (≥3% body surface area [BSA] or <3% BSA), current use of atleast 1 DMARD (yes or no), and number of prior failed (had an inadequateresponse to) biologic DMARDs (1 vs >1), except for subjects from Japan,for which randomization were stratified by extent of psoriasis (≥3% bodysurface area [BSA] or <3% BSA) only. Subjects were randomized in a2:2:1:1 ratio to one of four treatment groups:

-   -   Group 1: upadacitinib free base 15 mg QD (N=211)    -   Group 2: upadacitinib free base 30 mg QD (N=219)    -   Group 3: Placebo followed by upadacitinib free base 15 mg QD        (N=106)    -   Group 4: Placebo followed by upadacitinib free base 30 mg QD        (N=106)

No more than approximately 40% of subjects were enrolled with <3% BSAextent of psoriasis and no more than approximately 30% of subjects wereenrolled with prior failure of more than 1 biologic DMARD.

Subjects received oral study drug QD (upadacitinib free base 15 mg,upadacitinib free base 30 mg, or matching placebo) until the end of thestudy or until they discontinue study drug.

Subjects who were assigned to placebo at Baseline were preassigned toreceiving either upadacitinib free base 15 mg QD or upadacitinib freebase 30 mg QD starting at Week 24 in a 1:1 ratio. Subjects who completedthe Week 56 visit (end of Period 1) entered the long-term extensionportion of the study, Period 2 (total treatment up to approximately 3years). Subjects continued study treatment as assigned in Period 1.Subjects continued to receive upadacitinib free base 15 mg QD orupadacitinib free base 30 mg QD, respectively, in a blinded manner untilthe last subject completed the last visit of Period 1 (Week 56), whenstudy drug assignment in both periods will be unblinded to the sites,and subjects will be dispensed study drug in an open-label fashion untilthe completion of Period 2.

Subjects must have had inadequate response to ≥1 bDMARD prior to theScreening visit and must have discontinued all bDMARDs prior to thefirst dose of study drug. No background non-biologic DMARD therapy wasrequired during participation in this study. For subjects who are onnon-biologic DMARD therapy at baseline (methotrexate (MTX),sulfasalazine (SSZ), leflunomide (LEF), apremilast, hydroxychloroquine(HCQ), bucillamine or iguratimod), non-biologic DMARDs should have beenstarted ≥12 weeks prior to baseline visit, must be at stable dose for ≥4weeks prior to the first dose of study drug and remain at stable dosethrough Week 36 of the study; the non-biologic DMARD dose may bedecreased only for safety reasons. In addition, all subjects taking MTXshould take a dietary supplement of oral folic acid (or equivalent)throughout study participation.

At Week 16, rescue therapy will be offered to subjects classified asnon-responders (defined as not achieving at least 20% improvement ineither or both tender joint count (TJC) and swollen joint count (SJC) atboth Week 12 and Week 16) as follows: 1) add or modify doses ofnon-biologic DMARDs, NSAIDs, acetaminophen/paracetamol, low potencyopioid medications (tramadol or combination of acetaminophen and codeineor hydrocodone), oral corticosteroids and/or 2) receive

-   1 intra-articular, trigger point or tender point, intra-bursa, or    intra-tendon sheath corticosteroid injection for 1 peripheral joint,    1 trigger point, 1 tender point, 1 bursa, or 1 enthesis (Rescue    Therapy).

At Week 24, all subjects allocated to placebo at Baseline will beswitched to blinded upadacitinib (randomized at baseline to either 15 mgQD or 30 mg QD) treatment regardless of clinical response.

After the last subject completes the Week 24 study visit, an unblindedanalysis will be conducted for the purpose of initial regulatorysubmission. To maintain integrity of the trial during the blinded56-week period study sites and subjects will remain blinded until allsubjects have reached Week 56. A second unblinded analysis may beconducted for regulatory purposes after all subjects have completedPeriod 1. A final analysis will be conducted after all subjects havecompleted Period 2.

Primary and Secondary Endpoints

The primary efficacy endpoint is the proportion of subjects achievingAmerican College of Rheumatology (ACR) 20% response rate at Week 12. Theprimary and secondary clinical endpoints for the SELECT-PSA1 clinicalstudy (Example 35) and this study (SELECT-PSA2 clinical study; Example36) are further described in Example 37.

Study Population

Patients with active psoriatic arthritis and a previous inadequateresponse to at least one biologic DMARD.

Inclusion Criteria Include:

-   6. Adult male or female, at least ≥18 years old at Screening.-   7. Clinical diagnosis of PsA with symptom onset at least 6 months    prior to the Screening Visit and fulfillment of the Classification    Criteria for PsA (CASPAR).-   8. Subject has active disease at Baseline defined as ≥3 tender    joints (based on 68 joint counts) and ≥3 swollen joints (based on 66    joint counts) at Screening and Baseline Visits.-   9. Diagnosis of active plaque psoriasis or documented history of    plaque psoriasis.-   10. Subject has had an inadequate response (lack of efficacy after a    minimum 12-week duration of therapy) or intolerance to treatment    with at least 1 bDMARD.-   11. Subjects must have discontinued all bDMARDs prior to the first    dose of study drug. Subjects who need to discontinue bDMARDs prior    to the Baseline Visit to comply with this inclusion criterion must    follow the procedure specified below or at least five times the mean    terminal elimination half-life of a drug:    -   ≥4 weeks for etanercept;    -   ≥8 weeks for adalimumab, infliximab, certolizumab, golimumab,        abatacept, tocilizumab, and ixekizumab;    -   ≥16 weeks for secukinumab;    -   ≥12 weeks for ustekinumab;    -   ≥1 year for rituximab OR ≥6 months if B cells have returned to        pretreatment level or normal reference range (local lab) if        pretreatment levels are not available.-   12. Subject who is on current treatment with concomitant    non-biologic DMARDs at study entry must be on ≥2 non-biologic DMARDs    (except the combination of MTX and leflunomide) at the following    doses: MTX (≤25 mg/week), SSZ (≤3000 mg/day), leflunomide (LEF) (≤20    mg/day), apremilast (≤60 mg/day), HCQ (≤400 mg/day), bucillamine    (≤300 mg/day) and iguratimod (≤50 mg/day) for ≥12 weeks and at    stable dose for ≥4 weeks prior to the Baseline Visit. No other    DMARDs are permitted during the study.    -   Subjects who need to discontinue DMARDs prior to the Baseline        Visit to comply with this inclusion criterion must follow the        procedure specified below or at least five times the mean        terminal elimination half-life of a drug:        -   ≥8 weeks for LEF if no elimination procedure was followed,            or adhere to an elimination procedure (i.e., 11 days with            cholestyramine, or 30-day washout with activated charcoal or            as per local label);        -   ≥4 weeks for all others.-   13. Stable doses of NSAIDs, acetaminophen/paracetamol, low-potency    opiates (tramadol or combination of acetaminophen and codeine or    hydrocodone), oral corticosteroids (equivalent to prednisone≤10    mg/day), or inhaled corticosteroids for stable medical conditions    are allowed, but must have been at a stable dose for ≥1 weeks prior    to the Baseline Visit.-   14. Subjects must have discontinued all opiates (except for tramadol    or combination of acetaminophen and codeine or hydrocodone) at least    1 week and oral Traditional Chinese Medicine for at least 4 weeks    prior to the first dose of study drug.

Exclusion Criteria Include:

-   1. Prior exposure to any Janus Kinase (JAK) inhibitor (including but    not limited to ruxolitinib, tofacitinib, baricitinib, and    filgotinib)-   2. Current treatment with >2 non-biologic DMARDs or use of DMARDs    other than MTX, SSZ, LEF, apremilast, HCQ, bucillamine or iguratimod    or use of MTX in combination with LEF at Baseline-   3. History of fibromyalgia, any arthritis with onset prior to age 17    years, or current diagnosis of inflammatory joint disease other than    PsA (including, but not limited to rheumatoid arthritis, gout,    overlap connective tissue diseases, scleroderma, polymyositis,    dermatomyositis, systemic lupus erythematosus). Prior history of    reactive arthritis or axial spondyloarthritis including ankylosing    spondylitis and non-radiographic axial spondyloarthritis is    permitted if documentation of change in diagnosis to PsA or    additional diagnosis of PsA is made. Prior history of fibromyalgia    is permitted if documentation of change in diagnosis to PsA or    documentation that the diagnosis of fibromyalgia was made    incorrectly.

Analysis Windows

For each protocol-specified study visit, a target study day will beidentified to represent the corresponding visit along with a windowaround the target day. Windows will be selected in a non-overlappingfashion so that a collection date does not fall into multiple visitwindows. If a subject has two or more actual visits in one visit window,the visit closest to the target day will be used for analysis. If twovisits are equidistant from the target day, then the later visit will beused for analysis.

Results Up to and Including Week 24

As noted above, after the last subject completed the Week 24 studyvisit, an unblinded analysis was conducted for the purpose of initialregulatory submission.

A total of 642 subjects were randomized in this study, and 641 subjectsreceived double-blind study treatment, out of which 591 (92.1%)completed study drug through Week 12, and 543 (84.6%) completed studydrug through Week 24

The study met all primary and key secondary endpoints, with upadacitinib15 mg QD and 30 mg QD demonstrating significantly greater efficacy inPsA compared with placebo. See the below Tables as well as FIGS.22A-22BB. The time course of the primary endpoint ACR20 up to andincluding Week 24 is provided in FIG. 22A, and key secondary endpointsat ACR50. ACR70, and Proportion of Patients Achieving Minimal DiseaseActivity (MDA) Over 24 Weeks are provided in FIGS. 22B-22D. The timecourse of the change in baseline in Leeds Enthesitis Index (LEI) andsubjects with resolution of enthesitis (LEI=0) up to and including Week24 is presented in FIGS. 22E-22G. The time course of the change inbaseline in Leeds Dactylitis Index (LDI) and subjects with resolution ofdactylitis (LDI=0) up to and including Week 24 is presented in FIGS.22H-221. Data for other key secondary endpoints is provided in FIG. 21.

All p-values were statistically significant for both upadacitinib dosesas compared to placebo (graphical multiple testing procedure controllingthe overall type I error rate at the 0.05 level).

The primary analysis showed a significantly higher response rate in bothupadacitinib treatment groups as compared to the placebo group for theprimary endpoint. At week 12, significantly more patients achieved anACR20 response in the upadacitinib 15 mg and 30 mg arms versus theplacebo arm (56.9%, 63.8%, and 24.1%, respectively; p<0.001 for bothupadacitinib arms versus placebo). By week 2, ACR20 response wasachieved by more upadacitinib 15 mg- and 30 mg-treated patients (nominalp<0.001). The proportion of patients with ACR20 response continued toincrease over time in both treatment groups with the plateau of responseobserved at week 12 for the upadacitinib 30 mg group, whereas theproportion of patients with ACR20 response in the upadacitinib 15 mggroup increased through week 20, approximating the response rate in the30 mg dose group by the end of the placebo-controlled period. Responserates for upadacitinib 15 mg and upadacitinib 30 mg were 44.9% and 64.8%in the subgroup of patients who had failed >1 biologic DMARD and 55.8%and 66.7% in the subgroup of patients that were on monotherapy; theseresponses were similar to results in the overall population.Additionally, improvements in ACR50 and ACR70 were observed with bothupadacitinib doses versus placebo at week 12. From week 2 through week24, improvement from baseline in all components of ACR response wereobserved with upadacitinib 15 mg or 30 mg versus placebo. The efficacyof upadacitinib freebase 15 mg was demonstrated regardless of subgroupsevaluated including baseline BMI, baseline hsCRP, and number of priornon-biologic DMARDs (≤1 or >1).

The 15 mg and 30 mg doses of upadacitinib showed greater improvementversus placebo with respect to all key secondary endpoints. By week 12and through week 24, improvement in psoriasis was observed with bothupadacitinib doses versus placebo as measured by PASI 75/90/100 (at week16, p<0.001 for PASI 75 and nominal p<0.001 for PASI 90/100; nominalp<0.001 for all the other time points) and sIGA 0/1 (p<0.001 at week 16;nominal p<0.001 for weeks 12 and 24). The changes from baseline in SAPSwere greater for both upadacitinib arms versus placebo at weeks 16(p<0.001) and 24 (nominal p<0.001). Improvements in physical functionwere observed in patients on both doses of upadacitinib versus placebobased on the mean change from baseline in HAQ-DI from week 2 throughweek 24 (p<0.001 at week 12) and SF-36 PCS at weeks 12 (p<0.001) and 24(nominal p<0.001). The proportion of HAQ-DI responders (≥0.35improvement from baseline in HAQ-DI score) at Week 12 was 45% inpatients receiving upadacitinib freebase 15 mg QD and 27% in patientsreceiving placebo. Patients on both doses of upadacitinib reportedimprovements in fatigue as assessed by FACIT-F versus placebo at weeks12 (p<0.001) and 24 (nominal p<0.001). Mean improvements from baselinein morning stiffness were observed at weeks 12 and 24 (nominal p<0.001).Resolution of enthesitis using both the LEI and the SPARCC enthesitisindex and of dactylitis was reported in a higher proportion of patientson either dose of upadacitinib versus placebo from week 12 to week 24(nominal p<0.001). A higher proportion of patients receiving either doseof upadacitinib achieved MDA through week 24 versus placebo (p<001 atweek 24 nominal p<0.001 for weeks 12 and 16). Mean changes from baselinein the DAPSA score were greater with both upadacitinib doses versusplacebo through week 24 (nominal p<0.001 for all time points).

Health-related quality of life was assessed by SF-36. Patients receivingupadacitinib freebase 15 mg QD experienced significantly greaterimprovement from baseline in the Physical Component Summary scorecompared to placebo at Week 12. Greater improvement was also observed inthe Mental Component Summary score and all 8 domains of SF-36 (PhysicalFunctioning, Bodily Pain, Vitality, Social Functioning, Role Physical,General Health, Role Emotional, and Mental Health) compared to placebo.

TABLE 26A Demographics and Characteristics at Baseline UpadatitinibUpadacitinib Placebo 15 mg QD 30 mg QD N = 212 N = 211 N = 218 Female, n(%) 120 (56.6) 113 (53.6) 115 (52.8) Age (years) 54.1 ± 11.5 53.0 ± 12.053.0 ± 11.9 Race, n (%) White 186 (87.7) 183 (86.7) 196 (89.9) Black orAfrican American  7 (3.3)  5 (2.4)  5 (2.3) American Indian/AlaskaNative  0  3 (1.4)  0 Native Hawaiian or other Pacific Islander  1 (0.5) 1 (0.5)  1 (0.5) Asian  17 (8.0)  19 (9.0)  16 (7.3) Multiple  1 (0.5) 0  0 Duration of PsA symptoms (years) 14.6 ± 11.7 12.2 ± 8.8 13.3 ±10.8 Duration since PsA diagnosis (years) 11.0 ± 10.3  9.6 ± 8.4  9.7 ±8.7 Number of prior failed biologic DMARDs, n (%) 0^(a)  18 (8.5)  16(7.6)  17 (7.8) 1 135 (63.7) 126 (59.7) 130 (59.6) 2  35 (16.5)  35(16.6)  46 (21,1) ≥3  24 (11.3)  34 (16.1)  25 (11.5) Monotherapy, n (%)112 (52.8) 113 (53.6) 120 (55.0) Any non-biologic DMARD at baseline, n(%) MTX alone  75 (35.4)  74 (35.1)  73 (33.5) MTX + anothernon-biologic DMARD  7 (3.3)  6 (2.8)  5 (2.3) Non-biologic DMARD otherthan MTX  18 (8.5)  18 (8.5)  20 (9.2) MTX dose for patients withconcomitant MTX alone at baseline (mg/week) Mean 16.26 15.06 16,76Median 17.50 15.00 17.50 Steroid use at baseline, n (%)  24 (11.3)  22(10.4)  13 (6.0) NSAID use at baseline, n (%) 125 (59.0) 124 (58.8) 129(59.2) RF status positive, n (%)  6 (2.8)  11 (5.2)  8 (3.7) Anti-CCPstatus positive, n (%)  10 (4.7)  7 (3.3)  5 (2.3) TIC68 25.3 ± 17.624.9 ± 17.3 24.2 ± 15.9 SJC66 12.0 ± 8.9 11.3 ± 8.2 12.9 ± 9.4 hs-CRP >ULN^(b) (mg/ L), n (%) 121 (57.1) 126 (59.7) 128 (58.7) hs-CRP (mg/L)10.4 ± 18.5 11.2 ± 18.5 10.5 ± 17.2 HAQ-DI 1.23 ± 0.7 1.10 ± 0.6 1.19 ±0.7 Patient's assessment of pain (NRS 0-10)  6.6 ± 2.1  6.4 ± 2.1  6.2 ±2.2 BSA-psoriasis ≥3%, n (%) 131 (61.8) 130 (61.6) 131 (60.1) PASI (forbaseline BSA-Ps ≥3%) 11.7 ± 11.4 10.1 ± 9.2 8.9 ± 9.1 BSA-psoriasis >0%,n (%) 198 (93.4) 202 (95.7) 202 (92.7) BSA-psoriasis (for baseline >0%)12.8 ± 18.4 10.0 ± 15.7 10.0 ± 15.8 sIGA of psoriasis score, n (%) 0  17(8.0)  9 (4.3)  16 (7.3) 1  32 (15.1)  31 (14.7)  38 (17.4) 2  59 (27.8) 82 (38.9)  78 (35,8) 3  88 (41.5)  78 (37.0)  77 (35.3) 4  16 (7.5)  11(5.2)  9 (4.1) Presence of enthesitis LEI >0, n (%) 144 (67.9) 133(63.0) 152 (69.7) SPARCC Enthesitis Index >0, n (%) 173 (81.6) 172(81.5) 179 (82.1) Presence of dactylitis (defined as LDI >0), n (%)  64(30.2)  55 (26.1)  50 (22.9) Morning stiffness score^(c)  5.8 ± 2.5  6.0± 2.5  5.7 ± 2.7 Values are mean ± SD unless noted. ^(a)Patients withintolerance but not inadequate response to a biologic DMARD. ^(b)ULN =2.87 mg/L; ^(c)Morning stiffness score is the mean of BASDAI questions 5and 6; ^(d)Based on investigator opinion. Anti-CCP, anti-cycliccitrullinated peptide; ASDAS, Ankylosing Spondylitis Disease ActivityScore; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BSA,body surface area; DMARD, disease-modifying anti-rheumatic drug; HAQ-DI,Health Assessment Questionnaire-Disability index; hs-CRP,high-sensitivity C-reactive protein; LDI, Leeds Dactylitis-Index; LEI,Leeds Enthesitis Index; MTX, methotrexate; NRS, numeric rating scale;NSAID, nonsteroidal anti-inflammatory drug; PAST, Psoriasis AreaSeverity Index; Ps, psoriasis; PsA, psoriatic arthritis; QD, once daily;RE, rheumatoid factor; ULN, upper limit normal; SD, standard deviation;sIGA, Static Investigator Global Assessment; SJC, swollen joint count;SPARCC, Spondyloarthritis Research Consortium of Canada; TJC, tenderjoint count.

TABLE 26B Primary and Key Secondary Efficacy Endpoints SummaryStatistics UPA UPA % or LS Mean PLACEBO 15 MG QD 30 MG QD (P-Value)Endpoint^(a) N = 212 N = 211 N = 218 Primary ACR20 24.1% 56.9%(<0.0001*) 63.8% (<0.0001*) (Wk 12) Ranked Key 1. HAQ-DI −0.10 −0.30(<0.0001*) −0.41 (<0.0001*) Secondary (Wk 12) 2. sIGA 9.2% 36.8%(<0.0001*) 40.2% (<0.0001*) (Wk 16)^(b) 3. PASI 75 16.0% 52.1%(<0.0001*) 56.5% (<0.0001*) (Wk 16)^(c) 4. SF-36 PCS 1.62 5.2 (<0.0001*)7.1 (<0.0001*) (Wk 12) 5. FACIT-F 1.3 5.0 (<0.0001*) 6.1 (<0.0001*) (Wk12) 6. MDA 2.8% 25.1% (<0.0001*) 28.9% (<0.0001) (Wk 24) 7. SAPS −1.5−24.4 (<0.0001*) −29.7 (<0.0001*) (Wk 16) Other Key ACR50 4.7% 31.8%(<0.0001) 37.6% (<0.0001) Secondary (Wk 12) ACR70 0.5% 8.5% (<0.0001)16.5% (<0.0001) (Wk 12) ACR20 10.8% 32.7% (<0.0001) 33.5% (<0.0001) (Wk2) Note: The nominal p-values are provided in parentheses. *Statisticalsignificance using graphical multiple testing procedure controllingoverall type I error rate at the 0.05 level. ^(a)Results for binaryendpoints are based on NRI (net reclassification improvement) analysis.Results for minimal disease activity (MDA) at week 24 are based onnon-responder imputation with additional rescue handling, where subjectsrescued at Week 16 are imputed as non-responders. Results for continuousendpoints are based on mixed model for repeated measures (MMRM) modelwith fixed effects of treatment, visit, treatment-by-visit interaction,the stratification factor of current DMARD use (yes/no) and baselinemeasurement. ^(b)Summarized for subjects with baseline sIGA ≥2.^(c)Summarized for subjects with baseline BSA affected by psoriasis ≥3%.

TABLE 26C Additional Efficacy Endpoints for SELECT-PSA2: Summarized forsubjects with baseline BSA affected by psoriasis ≥ 3%^(a) UPA UPAPLACEBO 15 MG QD 30 MG QD Endpoint N = 131 N = 130 N = 131 PASI 90 (Wk16) 8.4% 34.6% (<0.0001) 45.0% (<0.0001) PASI 00 (WK 16) 6.1% 25.4%(<0.0001) 32.1% (<0.0001) ^(a)Full analysis set: N(PBO) = 212, N(UPA15)= 211, N(UPA30) = 218

TABLE 26D Exploratory endpoints UPA UPA Endpoint PLACEBO 15 MG QD 30 MGQD Resolution of enthesitis 20.1% 39.1% (<0.0001) 48.0% (<0.0001) atWeek 12 (defined as (N = 144) (N = 133) (N = 152) LEI = 0) Resolution ofdactylitis 35.9% 63.6% (<0.0001) 76.0% (<0.0001) at Week 12 (defined as(N = 64)  (N = 55)  (N = 50)  LDI = 0)

Additional data for ACR20, ACR50, and ACR70 response at Week 24, MDA atWeek 12, and resolution of enthesitis (LEI=0), and resolution ofdactylitis (LDI=0) at Week 24 is set forth in the below Table.

TABLE 26E Additional Clinical Responses UPA Placebo (N = 212) 15 mg QD(N = 211) Endpoint % % ACR20 (Wk 24) 20 59 ACR50 (Wk 24) 9 38 ACR70 (Wk24) 1 19 MDA (Wk 12) 4 17 Enthesitis resolution^(a) (Wk 15 43 24)Dactylitis resolution^(b) (Wk 28 58 24) Patients who discontinuedrandomized treatment or were missing data at week of evaluation wereimputed as non-responders in the analyses. For MDA, resolution ofenthesitis, and resolution of dactylitis at Week 24, the subjectsrescued at Week 16 were imputed as non-responders in the analyses.^(a)In patients with enthesitis at baseline (n = 144 and 133,respectively) ^(b)In patients with dactylitis at baseline (n = 64 and55)

Treatment with upadacitinib freebase 15 mg QD resulted in improvementsin individual ACR components, including tender/painful and swollen jointcounts, patient and physician global assessments of disease activity,HAQ-DI, pain assessment, and hsCRP compared to placebo. These resultsare summarized in FIGS. 22N-22S and 22V. Onset of efficacy was seen asearly as Week 2 for ACR20 and its components.

Through week 24, the rate of overall treatment-emergent AEs (TEAEs) washigher in the upadacitinib 30 mg arm and rates of serious AEs (SAEs) andTEAEs leading to discontinuation of trial drug were higher with bothupadacitinib doses versus placebo.

The most commonly reported TEAEs were upper respiratory tract infectionand nasopharyngitis in upadacitinib-treated patients. SAEs were reportedin four (1.9%) patients on placebo, twelve (5.7%) on upadacitinib 15 mg,and eighteen (8.3%) on upadacitinib 30 mg. Serious infections occurredin one patient each (0.5%) on placebo and upadacitinib 15 mg and six(2.8%) patients on upadacitinib 30 mg. Pneumonia was the most frequentlyreported serious infection (one patient on upadacitinib 15 mg and threepatients on upadacitinib 30 mg). Up to week 24, treatment-emergentopportunistic infections, excluding tuberculosis and herpes zoster,included one event each of candidiasis of the trachea and oropharyngealcandidiasis, both with upadacitinib 30 mg. Herpes zoster was reported intwo, three, and eight patients in the placebo, upadacitinib 15 mg and 30mg arms, respectively; none of the cases were serious. One patient onupadacitinib 15 mg and two patients on upadacitinib 30 mg had cutaneousdisseminated herpes zoster. No cases of herpes zoster with centralnervous system involvement were observed. Hepatic disorders werereported in three (1.4%) patients on placebo, four (1.9%) onupadacitinib 15 mg, and eighteen (8.3%) on upadacitinib 30 mg; most wereasymptomatic liver enzyme elevations.

Malignancies were reported in three patients in each upadacitinib arm(upadacitinib 15 mg: one basal cell carcinoma, one prostate cancer, onerectal cancer; upadacitinib 30 mg: one rectal adenocarcinoma, oneovarian and endometrial cancer, and one basal cell carcinoma) and nonein the placebo arm. The time to event onset for these malignant eventswas <6 months.

There were no adjudicated gastrointestinal perforations reported throughweek 24. One case of major adverse cardiovascular event (MACE; 0.5%,non-fatal myocardial infarction) and one case of venous thromboembolicevent (VTE; 0.5%; pulmonary embolism) were reported in the upadacitinib15 mg arm; both patients had at least one risk factor (e.g., obesity,hypertension, or hypercholesterolemia) for MACE or VTE, respectively.Over the 24-week period, one death was reported in the placebo armrelated to a motor vehicle accident.

Generally, mean hemoglobin, neutrophil, lymphocyte, and platelet levelsremained within normal limits from baseline through week 24 in alltreatment arms. There were two patients with Grade 3 decreases inhemoglobin values in the upadacitinib 30 mg arm. Grade 3 decreases inneutrophils were reported in one patient on placebo (0.5%), two patientson upadacitinib 15 mg (1.0%), and four patients on upadacitinib 30 mg(1.8%). No patients had Grade 4 decreases in platelets, leukocytes,neutrophils, or lymphocytes.

Isolated Grade 3 increases in alanine aminotransferase or aspartateaminotransferase were observed in ≤1% of the patients among thetreatment arms, and no Grade 4 increases were observed. No Hy's lawcases were reported. Grade 3 increases in CPK values were reported inone (0.5%), one (0.5%), and five (2.3%) patients in the placebo, andupadacitinib 15 mg and 30 mg arms, respectively. Grade 4 increases inCPK values were reported in two patients with placebo and one patientwith upadacitinib 15 mg. None led to discontinuation of trial drug andthere were no events of rhabdomyolysis. Slight mean elevations inlow-density lipoprotein cholesterol (LDL-C) and high-density lipoproteincholesterol (HDL-C) were observed in the upadacitinib arms versus theplacebo arm. The ratios of LDL-C:HDL-C and Total cholesterol: HDL-Cgenerally remained constant through week 24.

Upadacitinib as a Promising Therapy for the Treatment of PsA

A review of the placebo corrected data for upadacitinib and the JAKsmall molecule inhibitor Tofacitinib (approved for the lower (5 mg BID)dose in the treatment of PsA) for key primary and secondary endpoints,while not a head to head comparison, suggests that upadacitinib 15 mg QDand 30 mg QD shows decided promise for the more difficult to achieveendpoints of minimal disease activity (MDA), as well as psoriasisendpoints PASI 75 or PASI 90, as well as certain ACR components (e.g.,ACR2/50/70). Furthermore, it was observed that this efficacy, onceachieved, was sustained or improved over time.

TABLE 26F Placebo Corrected Responses (% response/placebo response)Upadacitinib Select PsA2 Tofacitinib Ixekizumamb Upa 15 mg Upa 30 mgOpal Beyond Spirit P2 QD QD Tofa 5 mg Tofa 10 mg IXE 80 mg IXE 80 WeekWeek BID BID Q4W mg Q2W Endpoint 12/16/24 12/16/24 Week 12 Week 12 Week24 Week 24 ACR20 Week 12 Week 12 26% 23% 34% 29% 33%   40% (50%/24%,(47%/24%, (53%/19%, (48%/19%, (56.9%/24.1%, (63.8%/24.1%, p ≤ 0.001) p ≤0.001) p ≤ 0.001) p ≤ 0.001) p ≤ 0.001) p ≤ 0.001) ACR50 Week 12 Week 1215% 13% 30% 28% 27% 37.6% (30%/15%, (28%/15%, (35%/5%, (33%/5%,(31.8%/4.7%, (37.6%/4.7%, p ≤ 0.01) p ≤ 0.01) p ≤ 0.001) p ≤ 0.001) p ≤0.001) p ≤ 0.001) ACR70 Week 12 Week 12  7%  4% 22% 12%  8%   16%(17%/10%) (14%/10%) (22%/0%, (12%/0%, (8.5%/0.5%, (16.5%/0.5%, p ≤0.001) p ≤ 0.001) p ≤ 0.001) p ≤ 0.001) PASI 75 Week 16 Week 16 7% 29%41% 45% 36%   41% (21%/14%) (43%/14%) (56%/15%, (60%/15%, (52%/16%,(57%/16%, p ≤ 0.001) p ≤ 0.001) p ≤ 0.001) p ≤ 0.001) MDA Week 24 Week24  8%  6% 25% 21% 22%   26% (23%/15%) (21%/15%) (28%/3%, (24%/3%,(25%/3%, (29%/3%, p ≤ 0.001) p ≤ 0.001) p ≤ 0.001) p ≤ 0.001)

Example 37: SELECT-PSA1 (Example 35) and SELECT-PSA2 (Example 36)Clinical Endpoints Primary Endpoint for PsAS and PsA2 Studies

The primary efficacy endpoint is the proportion of subjects achievingAmerican College of Rheumatology (ACR) 20% response rate at Week 12.ACR20 response rate was determined based on a 20% or greater improvementin tender and swollen joint counts (TJC and SJC) and ≥3 of the 5measures of Patient's Global Assessment of Pain (Pt Pain) NumericalRating Scale (NRS), Patient's Global Assessment (PtGA)-Disease ActivityNumerical Rating Scale (NRS), Physician Global Assessment (PGA)-DiseaseActivity Numerical Rating Scale (NRS), Health AssessmentQuestionnaire-Disability Index (HAQ-D), or High-Sensitivity C ReactiveProtein (hs-CRP).

Key Secondary Endpoints for PsA1 and PsA2 Studies

The key multiplicity adjusted secondary efficacy endpoints (each dose ofupadacitinib versus placebo unless noted) are:

TABLE 27A Study Key Endpoints PsA-1 Study Key Secondary Endpoints PsA-2Study Key Secondary Endpoints 1 Change from baseline in HealthAssessment Change from baseline in Health AssessmentQuestionnaire-Disability Index (HAQ-DI) Questionnaire-Disability Index(HAQ-DI) at at Week 12; Week 12; 2 Proportion of subjects achieving astatic Proportion of subjects achieving a static Investigator GlobalAssessment (sIGA) of Investigator Global Assessment (sIGA) of Psoriasisof 0 or 1 and at least a 2-point Psoriasis of 0 or 1 and at least a2-point improvement from baseline at Week 16 (for improvement frombaseline at Week 16 (for subjects with baseline sIGA ≥ 2); subjects withbaseline sIGA ≥ 2); 3 Psoriasis Area Severity Index (PASI) 75 PsoriasisArea Severity Index (PASI) 75 response at Week 16 (for subjects with ≥3%response at Week 16 (for subjects with ≥3% Body Surface Area (BSA)psoriasis at Body Surface Area (BSA) psoriasis at baseline); baseline);4 Change from baseline in Sharp/van der Heijde Score (SHS) at Week 24; 5Proportion of subjects achieving MDA Proportion of subjects achievingMDA (Minimal Disease Activity) at Week 24; (Minimal Disease Activity) atWeek 24; 6 Change from baseline in Leeds Enthesitis Index (LEI) at Week24; 7 Change from baseline in Leeds Dactylitis Index (LDI) at Week 24; 8American College of Rheumatology (ACR) 20 response rate at Week 12(non-inferiority of upadacitinib vs adalimumab); 9 Change from baselinein 36-item Short Form Change from baseline in 36-Item Short Form HealthSurvey (SF-36) at Week 12; Health Survey (SF-36) at Week 12; 10 AmericanCollege of Rheumatology (ACR) 20 response rate at Week 12 (superiorityof upadacitinib vs. adalimumab); 11 Change from baseline in Patient'sGlobal Assessment of Pain Numerical Rating Scale (NRS) at Week 12(superiority of upadacitinib vs. adalimumab); 12 Change from baseline inHealth Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12(superiority of upadacitinib vs. adalimumab); 13 Change from baseline inFunctional Change from baseline in Functional Assessment of ChronicIllness Therapy- Assessment of Chronic Illness Therapy- Fatigue(FACIT-Fatigue) Questionnaire at Fatigue (FACIT-Fatigue) Questionnaireat Week 12; and Week 12.; and 14 Change from baseline in Self-Assessmentof Change from baseline in Self-Assessment of Psoriasis Symptoms (SAPS)Questionnaire at Psoriasis Symptoms (SAPS) Questionnaire at Week 16.Week 16

Additional key secondary efficacy endpoints (each dose of upadacitinibversus placebo) are:

TABLE 27B Additional Key Secondary Efficacy Endpoints PsA-1 StudyAdditional Key PsA-2 Study Additional Key Secondary Endpoints SecondaryEndpoints 1 ACR50/70 response at Week 12; ACR50/70 response at Week 12;2 ACR20 response at Week 2 ACR20 response at Week 2

The proportion of subjects achieving Minimal Disease Activity (MDA) aredetermined based on subjects fulfilling 5 of 7 outcome measures: TJC≤1;SJC≤1; PASI≤1 or BSA-Ps≤3%; Patient's Global Assessment of Pain (PtPain) NRS≤1.5 (0-10 NRS); PtGA-Disease Activity NRS≤2 (0-10 NRS); HAQ-DIscore≤0.5; and LEI≤1. See. e.g., Coates L C, Kavanaugh A, Mease P J, etal; Group for Research and Assessment of Psoriasis and PsoriaticArthritis (GRAPPA) 2015 treatment recommendations for psoriaticarthritis. Arthritis Rheumatol. 2016; 68(5):1060-71.

ACR20/50/70 response rates are determined based on 20%/50%/70% orgreater improvement in TJC and SJC and ≥3 of the 5 measures of Patient'sGlobal Assessment of Pain (Pt Pain) NRS, PtGA-Disease Activity NRS,PGA-Disease Activity NRS, HAQ-DI, or hs-CRP.

Additional Secondary Endpoints for PsA1 and PsA2 Studies

The following outcome measures were assessed in subjects treated withupadacitinib as compared to placebo and adalimumab at scheduled timepoints other than those specified for the primary and key secondaryvariables:

TABLE 27C Additional Secondary Endpoints PsA-1 Study AdditionalSecondary PsA-2 Study Additional Secondary Endpoints Endpoints 1Proportion of subjects with no radiographic progression (defined aschange from baseline in SHS ≤ 0); 2 Change from baseline in individualChange from baseline in individual components of ACR response:components of ACR response: (i) Change from baseline in Tender (i)Change from baseline in Tender Joint Count Joint Count (TJC) (0-68);(ii) Change (TJC) (0-68); (ii) Change from baseline in from baseline inSwollen Joint Count Swollen Joint Count (SJC) (0-66); (iii) (SJC)(0-66); (iii) Change from Change from baseline in Physician Globalbaseline in Physician Global Assessment (PGA)-Disease ActivityAssessment (PGA)-Disease Activity Numerical Rating Scale (NRS); (iv)Change Numerical Rating Scale (NRS); (iv) from baseline in Patient'sGlobal Assessment Change from baseline in Patient's (PtGA)-DiseaseActivity Numerical Rating Global Assessment (PtGA)-Disease Scale (NRS);(v) Change from baseline in Activity Numerical Rating Scale (NRS);Patient's Global Assessment of Pain Numerical (v) Change from baselinein Patient's Rating Scale (NRS); (vi) Change from baseline GlobalAssessment of Pain Numerical in Health Assessment Questionnaire- RatingScale (NRS); (vi) Change from Disability Index (HAQ-DI); (vii) Changefrom baseline in Health Assessment: baseline in High-Sensitivity CReactive Protein Questionnaire-Disability index (HAQ- (hs-CRP); DI);(vii) Change from baseline in High-Sensitivity C Reactive Protein (hs-CRP); 3 ACR 20/50/70 response rates; ACR 20/50/70 response rates; 4Change from baseline in Leeds Change from baseline in Leeds DactylitisDactylitis Index (LDI); Index (LDI); 5 Change from baseline indactylitis Change from baseline in dactylitis count; count; 6 Proportionof subjects with resolution of Proportion of subjects with resolution ofdactylitis; dactylitis; Change from baseline in Leeds Change frombaseline in Leeds Enthesitis Enthesitis Index (LEI); Index (LEI); 8Proportion of subjects with resolution of Proportion of subjects withresolution of enthesitis sites included in the Leeds enthesitis sitesincluded in the Leeds Enthesitis Enthesitis Index (LEI); Index (LEI); 9Change from baseline in Change from baseline in SpondyloarthritisSpondyloarthritis Research Consortium Research Consortium of Canada(SPARCC) of Canada (SPARCC) Enthesitis Index; Enthesitis Index; 10Proportion of subjects with resolution of Proportion of subjects withresolution of enthesitis sites included in the enthesitis sites includedin the Spondyloarthritis Research Consortium Spondyloarthritis ResearchConsortium of of Canada (SPARCC) Enthesitis Index; Canada (SPARCC)Enthesitis Index; 11 Change from baseline in total enthesitis Changefrom baseline in total enthesitis count; count; 12 Proportion ofsubjects with resolution of Proportion of subjects with resolution ofenthesitis; enthesitis; 13 PASI 75/90/100 response rates (for PASI75/90/100 response rates (for subjects subjects with ≥3% Body SurfaceArea with ≥3% Body Surface Area (BSA) psoriasis (BSA) psoriasis atbaseline); at baseline); 14 Proportion of subjects achieving a staticProportion of subjects achieving a static Investigator Global Assessmentof Investigator Global Assessment of Psoriasis Psoriasis (sIGA) score of0 or 1 and at (sIGA) score of 0 or 1 and at least a 2-point least a2-point improvement from improvement from baseline; baseline; 15 BSA-Ps;BSA-Ps. 16 Change from baseline in Modified Change from baseline inModified Psoriatic Psoriatic Arthritis Response Criteria ArthritisResponse Criteria (PsARC); (PsARC); 17 Change from baseline in DiseaseChange from baseline in Disease Activity Activity Score 28 (DAS28)(CRP); Score 28 (DAS28) (CRP); 18 Change from baseline in DAS28 (ESR);Change from baseline in DAS28 (ESR); 19 Change from baseline in PsADisease Change from baseline in PsA Disease Activity Activity Score(PASDAS); Score (PASDAS); 20 Change from baseline in Disease Change frombaseline in Disease Activity In Activity In Psoriatic Arthritis (DAPSA)Psoriatic Arthritis (DAPSA) score; score; 21 Change from baseline inShort Form 36 Change from baseline in Short Form 36 (SF- (SF-36) HealthQuestionnaire; 36) Health Questionnaire; 22 Change from baseline inFunctional Change from baseline in Functional Assessment of ChronicIllness Therapy Assessment of Chronic Illness Therapy (FACIT)-FatigueQuestionnaire; (FACIT)-Fatigue Questionnaire; 23 Change from baseline inEuroQol-5- Change from baseline in EuroQol-5- Dimensions-5-Levels(EQ-5D-5L) Dimensions-5-Levels (EQ-5D-5L) Questionnaire; Questionnaire;24 Change from baseline in Work Change from baseline in WorkProductivity Productivity and Activity Impairment and ActivityImpairment (WPM) (WPAI) Questionnaire; Questionnaire; 25 Change frombaseline in Health Change from baseline in Health Resource ResourceUtilization (HRU) Utilization (HRU) Questionnaire; Questionnaire; 26Change from baseline in Self- Change from baseline in Self-Assessment ofAssessment of Psoriasis Symptoms Psoriasis Symptoms (SAPS)Questionnaire; (SAPS) Questionnaire; 27 Change from baseline in BathChange from baseline in Bath Ankylosing Ankylosing Spondylitis DiseaseSpondylitis Disease Activity Index (BASDAI); Activity Index (BASDAI); 28Bath Ankylosing Spondylitis Disease Bath Ankylosing Spondylitis DiseaseActivity Activity Index (BASDAI) 50 response Index (BASDAI) 50 responserates; rates; 29 Change from baseline in Morning Change from baseline inMorning stiffness stiffness (mean of BASDAI Questions 5 (mean of BASDAIQuestions 5 and 6); and 6); 30 Change from baseline in Ankylosing Changefrom baseline in Ankylosing Spondylitis Disease Activity ScoreSpondylitis Disease Activity Score (ASDAS); (ASDAS); 21 Proportion ofsubjects with Ankylosing Proportion of subjects with AnkylosingSpondylitis Disease Activity Score Spondylitis Disease Activity Score(ASDAS) (ASDAS) Inactive Disease; Inactive Disease; 32 Proportion ofsubjects with Ankylosing Proportion of subjects with AnkylosingSpondylitis Disease Activity Score Spondylitis Disease Activity Score(ASDAS) (ASDAS) Major Improvement; Major Improvement; 33 Proportion ofsubjects with Ankylosing Proportion of subjects with AnkylosingSpondylitis Disease Activity Score Spondylitis Disease Activity Score(ASDAS) (ASDAS) Clinically important Clinically Important Improvement;Improvement; 34 Proportion of subjects achieving a Proportion ofsubjects achieving a clinically clinically meaningful improvement inmeaningful improvement in Health Assessment Health AssessmentQuestionnaire- Questionnaire-Disability Index (HAQ-DI) Disability Index(HAQ-DI) (≥0.35). (≥0.35).

Example 38: A Phase 3 Randomized, Placebo-Controlled, Double-BlindProgram to Evaluate Efficacy and Safety of Upadacitinib in AdultSubjects with Axial Spondyloarthritis (Select AXIS 2)

The safety and efficacy data from the Phase 2/3 study (as described inExamples 2) show a favorable benefit:risk profile for upadacitinib andsupport the continued investigation of upadacitinib in adult subjectswith active axSpA who had an inadequate response to biologicdisease-modifying anti-rheumatic drug therapy (bDMARD-IR) (Study 1) andin adult subjects with active nr-axSpA (Study 2).

axSpA (Study 2).

The Phase 3 clinical study plan is set forth in FIG. 2.

Adult Subjects with Active Ankylosing Spondylitis (AS) Who had anInadequate Response to Biologic Disease-Modifying Anti-Rheumatic DrugTherapy (bDMARD-IR) (Study 1)

To evaluate the safety, tolerability, and efficacy of upadacitinibcompared with placebo on reduction of signs and symptoms in adultsubjects with active ankylosing spondylitis (AS) who had an inadequateresponse to biologic disease-modifying anti-rheumatic drug therapy(bDMARD-IR).

Study 1 (main study) is comprised of a 35-day Screening Period: a14-week randomized, double-blind, parallel-group, placebo-controlledperiod (the Double-Blind Period); a 90-week open-label, long-termextension period (the Open-Label Extension Period); and a 30-dayFollow-Up Visit (F/U Visit). Group 1: upadacitinib free base 15 mg QD:Group 2: placebo QD. Subjects in the placebo group will be switched toupadacitinib free base 15 mg QD at Week 14 in the Open-Label ExtensionPeriod for Study 1.

Eligible subjects will be adult females and males who are at least 18years of age at Screening with a clinical diagnosis of AS, meet themodified New York Criteria for AS, and are without total spinalankylosis (Study 1, bDMARD-IR AS). Eligible study subjects must have aBath Ankylosing Spondylitis Disease Activity Index score≥4 and aPatient's Assessment of Total Back Pain score (Total Back Pain score)≥4based on a 0-10 numerical rating scale at the Screening and BaselineVisits.

For Study 1 (bDMARD-IR AS), subjects with prior exposure to 1 biologicdisease-modifying anti-rheumatic drug (bDMARD) (either 1 tumor necrosisfactor [TNF] inhibitor or 1 interleukin [IL]-7 inhibitor) may beenrolled, and the subject must have discontinued the bDMARD due toeither intolerance or lack of efficacy. Prior exposure to a 2^(nd)bDMARD is allowed for no more than 30% of subjects if the reason fordiscontinuation was not due to lack of efficacy. Subjects who have hadlack of efficacy to both a TNF inhibitor and IL-17 inhibitor are noteligible.

Study 1 Primary Endpoint

The primary endpoint is the proportion of subjects achieving an ASAS40response at Week 14. Secondary endpoints for Study 1 are describedbelow.

Adult Subjects with Active Non-Radiographic Axial Spondyloarthritis(Nr-axSpA) (Study 2)

To evaluate the safety, tolerability, and efficacy of upadacitinibcompared with placebo on reduction of signs and symptoms in adultsubjects with active non-radiographic axial spondyloarthritis(nr-axSpA).

Study 2 (nr-axSpA) is comprised of a 35-day Screening Period; a 52-weekrandomized, double-blind, parallel-group, placebo-controlled period (theDouble-Blind Period): a 52-week open-label, long-term extension period(the Open-Label Extension Period); and a 30-day F/U Visit. Group 1:upadacitinib free base 15 mg QD: Group 2: placebo QD.

Subjects in the placebo group will be switched to upadacitinib free base15 mg QD at Week 52 in the Open-Label Extension Period for Study 2(nr-axSpA).

Eligible subjects will be adult females and males who are at least 18years of age at Screening with a clinical diagnosis of nr-axSpAfulfilling the 2009 ASAS classification criteria for axSpA but notmeeting the radiologic criterion of the modified New York criteria forAS and have objective signs of active inflammation on magnetic resonanceimaging of sacroiliac joints or based on high sensitivity C-reactiveprotein>upper limit of normal (Study 2, nr-axSpA). Eligible studysubjects must have a Bath Ankylosing Spondylitis Disease Activity Indexscore≥4 and a Patient's Assessment of Total Back Pain score (Total BackPain score)≥4 based on a 0-10 numerical rating scale at the Screeningand Baseline Visits. Subject must have objective signs of activeinflammation on MRI of SI joints or hsCRP>ULN at screening.

For Study 2 (nr-axSpA), subjects with prior failure of nonsteroidalanti-inflammatory drugs (NSAIDs) may be enrolled, and prior treatmentwith at most 1 bDMARD (either 1 TNF inhibitor or 1 IL-17 inhibitor) isallowed in a subset of subjects (at least 25%, but not exceeding 35% oftotal enrolled subjects). Subjects with prior exposure to 1 bDMARD(either 1 tumor necrosis factor [TNF] inhibitor or 1 interleukin [IL]-17inhibitor) may be enrolled, and the subject must have discontinued thebDMARD due to either intolerance or lack of efficacy. Prior exposure toa 2^(nd) bDMARD is allowed for no more than 30% of subjects if thereason for discontinuation was not due to lack of efficacy. Subjects whohave had lack of efficacy to both a TNF inhibitor and IL-17 inhibitorare not eligible.

Study 2 Primary Endpoints

The primary endpoint for European Union [EU]/European Medicines Agency[EMA] regulatory purposes is the proportion of subjects achieving anASAS40 response at Week 14.

The primary endpoint for US/Food and Drug Administration [FDA]regulatory purposes is the proportion of subjects achieving an ASAS40response at Week 52.

Secondary endpoints for Study 2 are described below.

Study 1: bDMARD-IR AS Specific Criteria

-   -   1. Subject must have a clinical diagnosis of AS and subjects        must meet the modified New York criteria for AS.    -   2. Subject must not have total spinal ankylosis.    -   3. Subjects with prior exposure to 1 bDMARD (either 1 tumor        necrosis factor [TNF] inhibitor or 1 interleukin [IL]-17        inhibitor) may be enrolled, and the subject must have        discontinued the bDMARD due to either intolerance or lack of        efficacy. Prior exposure to a 2^(nd) bDMARD is allowed for no        more than 30% of subjects if the reason for discontinuation was        not due to lack of efficacy. Subjects who have had lack of        efficacy to both a TNF inhibitor and IL-17 inhibitor are not        eligible.

Study 2: Nr-axSpA-Specific Criteria

-   -   1. Subject must have a clinical diagnosis of nr-axSpA fulfilling        the 2009 ASAS classification criteria for axSpA but not meeting        the radiologic criterion of the modified New York criteria for        AS.    -   2. Subjects with or without prior exposure to a bDMARD may be        enrolled.        -   For the subset of subjects with prior bDMARD exposure (at            least 25%, but not exceeding 35% of total enrolled            subjects), prior treatment with at most 1 bDMARD (either 1            TNF inhibitor or 1 IL-17 inhibitor) is allowed, and the            subject must have discontinued the bDMARD due to either            intolerance or lack of efficacy. Subjects who have had lack            of efficacy to both a TNF inhibitor and IL-17 inhibitor are            not eligible.    -   3. Subject must have objective signs of active inflammation on        MRI of SI joints or hsCRP>ULN at screening.

The Following Eligibility Criteria are Applicable for Study 1 and Study2:

-   -   1. Subject must be an adult male or female, at least 18 years of        age at Screening.    -   2. Subject must meet the following scores at Screening and        Baseline Visits: BASDAI score≥4 and Total Back Pain score≥4        based on a 0-10 NRS.    -   3. Subject has had an inadequate response to at least 2 NSAIDs        over an at least 4-week period in total at maximum recommended        or tolerated doses, or subject has an intolerance to or        contraindication for NSAIDs.    -   4. The washout period for bDMARDs prior to the first dose of        study drug is specified below:        -   ≥4 weeks for etanercept;        -   ≥8 weeks for adalimumab, infliximab, certolizumab,            golimumab, abatacept, tocilizumab, and ixekizumab;        -   ≥12 weeks for ustekinumab;        -   ≥16 weeks for secukinumab;        -   ≥1 year for rituximab OR ≥6 months if B cells have returned            to pre-treatment level or normal reference range (central            lab) if pre-treatment levels are not available;        -   ≥12 weeks or at least 5 times the mean terminal elimination            half-life, whichever is longer, for other bDMARDs.    -   5. If entering the study on the following concomitant csDMARDs        (MTX (≤25 mg/week); or Sulfasalazine (SSZ) (≤3 g/day); or        Hydroxychloroquine (≤400 mg/day); or Chloroquine (≤400 mg/day);        or Leflunomide (≤20 mg/day); or Apremilast (≤60 mg/day)),        subject must be on a stable dose as indicated below for at least        28 days prior to the Baseline Visit. A combination of up to 2        background csDMARDs is allowed EXCEPT the combination of        methotrexate (MTX) and leflunomide.    -   6. If entering the study on concomitant oral corticosteroids,        subject must be on a stable dose of prednisone (≤10 mg/day) or        oral corticosteroid equivalent for at least 14 days prior to the        Baseline Visit.    -   7. If entering the study on concomitant NSAIDs, tramadol,        combination of acetaminophen/paracetamol and codeine or        combination of acetaminophen/paracetamol and hydrocodone, and/or        non-opioid analgesics, subject must be on stable dose(s) for at        least 14 days prior to the Baseline Visit.    -   8. Subject must not have been exposed to any JAK inhibitor.    -   9. Subject must not have used the following prohibited        concomitant treatments within the specified timeframe prior to        Baseline Visit:        -   Intra-articular joint injections, spinal/paraspinal            injection(s), or parenteral administration of            corticosteroids within 28 days prior to the Baseline Visit.            Inhaled or topical corticosteroids are allowed;        -   Any other csDMARDs (other than those allowed per eligibility            criterion), including thalidomide, within 28 days or 5            half-lives (whichever is longer) of the drug prior to the            Baseline Visit;        -   Opioid analgesics (except for combination of            acetaminophen/paracetamol and codeine or combination of            acetaminophen/paracetamol and hydrocodone which are allowed)            within    -   14 days prior to the Baseline Visit.    -   10. Subject must not have received a live vaccine within 28 days        (or longer if required locally) prior to the first dose of study        drug or have expected need of live vaccination during study        participation including at least 30 days (or longer if required        locally) after the last dose of study drug.    -   11. Subject must have no systemic use of known strong cytochrome        P450 3A (CYP3A) inhibitors from Screening through the end of        study drug administration or strong CYP3A inducers 30 days prior        to study drug administration through the end of study drug        administration. Subjects must not use herbal therapies or other        traditional medicines with unknown effects on CYP3A from        Screening through the end of study drug administration.    -   12. Subject must not have been treated with any investigational        drug of chemical or biologic nature within a minimum of 30 days        or 5 half-lives of the drug (whichever is longer) prior to the        first dose of study drug or is currently enrolled in another        interventional study.    -   13. Subject must not have a history of an allergic reaction or        significant sensitivity to constituents of the study drug (and        its excipients) and/or other products in the same class.

Study 1 and Study 2 Secondary Endpoints

The key multiplicity-controlled secondary endpoints at Week 14 are asfollows:

TABLE 28A Study 1 (active AS) Study 2 (active nr-axSpA) 1 Change fromBaseline in Ankylosing Change from Baseline in Ankylosing SpondylitisDisease Activity Score Spondylitis Disease Activity Score (ASDAS)(ASDAS) at Week 14 at Week 14 2 Change from Baseline in magneticresonance Change from Baseline in magnetic resonance imaging (MRI)Spondyloarthritis Research imaging (MRI) Spondyloarthritis ResearchConsortium of Canada (SPARCC) score Consortium of Canada (SPARCC) score(SI (spine) at Week 14 (MRI-Spine SPARCC) joints) at Week 14 (MRI-JointsSPARCC) 3 Proportion of subjects with ASAS partial Proportion ofsubjects with ASAS partial remission (PR) (an absolute score of ≤ 2units remission (PR) On absolute score of ≤ 2 units for each of the 4domains identified in for each of the 4 domains identified in ASAS40) atWeek 14 ASAS40) at Week 14 4 Proportion of subjects with Bath AnkylosingProportion of subjects with Bath Ankylosing Spondylitis Disease ActivityIndex Spondylitis Disease Activity Index (BASDAI) (BASDAI) 50 responseat Week 14 50 response at Week 14 5 Change from Baseline in BathAnkylosing Change from Baseline in Bath Ankylosing SpondylitisFunctional Index (BASFI) at at Spondylitis Functional Index (BASFI) atWeek 14 (Function) Week 14 (Function) 6 Change from Baseline inAnkylosing Change from Baseline in Ankylosing Spondylitis Quality ofLife (ASQoL) at Spondylitis Quality of Life (ASQoL) at Week Week 14 14 7Change from Baseline in ASAS Health Index Change from Baseline in ASASHealth Index (HI) at Week 14 (HI) at Week 14 8 Change from Baseline inMaastricht Change from Baseline in Maastricht Ankylosing SpondylitisEnthesitis Score Ankylosing Spondylitis Enthesitis Score (MASES) at Week14 (Enthesitis) (MASES) at Week 14 (Enthesitis) 9 Change from Baselinein Linear Bath Change from Baseline in Linear Bath AnkylosingSpondylitis Metrology Index Ankylosing Spondylitis Metrology Index(BASMI_(lin)) at Week 14 (Mobility) (BASMI_(lin)) at Week 14 (Mobility)

Additional key secondary endpoints at Week 14 include:

TABLE 28B Study 1 (active AS) Study 2 (active nr-axSpA) 1 Proportion ofsubjects with Proportion of subjects with ASAS20 response at Week 14ASAS20 response at Week 14 2 Change from Baseline in Change fromBaseline in MRI MRI SPARCC score SPARCC score (spine) at (SI joints) atWeek 14 Week 14 3 Proportion of subjects rescued between Week 24 andWeek 52

Additional Study 1 and Study 2 Endpoints

Additional endpoints are the following measurements assessed at timepoints other than those specified for the primary and key secondaryvariables are as follows:

TABLE 28C Study 1 (active AS) Study 2 (active nr-axSpA) 1 Proportion ofsubjects with ASAS20 response Proportion of subjects with ASAS20response 2 Proportion of subjects with ASAS40 response Proportion ofsubjects with ASAS40 response 3 Proportion of subjects with ASAS PRProportion of subjects with ASAS PR 4 Proportion of subjects with ASDASInactive Proportion of subjects with ASDAS Inactive Disease (ASDAS score< 1.3) Disease (ASDAS score < 1.3) 5 Proportion of subjects with ASDASLow Proportion of subjects with ASDAS Low Disease (ASDAS score < 2.1)Disease (ASDAS score < 2.1) 6 Proportion of subjects with ASDAS MajorProportion of subjects with ASDAS Major Improvement (a change fromBaseline of Improvement (a change from Baseline of ≤−2.0) ≤−2.0) 7Proportion of subjects with ASDAS Clinically Proportion of subjects withASDAS Important Improvement (a change from Clinically ImportantImprovement (a Baseline of ≤−1.1) change from Baseline of ≤−1.1) 8Proportion of subjects with Discontinuation of Proportion of subjectswith Discontinuation opioids among subjects with opioid use at ofopioids among subjects with opioid use at Baseline Baseline 9 Changefrom Baseline in ASAS HI Change from Baseline in ASAS HI 10 Change fromBaseline in ASDAS Change from Baseline in ASDAS 11 Change from Baselinein ASQoL Change from Baseline in ASQoL 12 Change from Baseline in BASDAIand Change from Baseline in BASDAI and BASDAI Questions including meanof BASDAI Questions including mean of question 5 and 6 of the BASDAIquestion 5 and 6 of the BASDAI 13 Change from Baseline in BASFI Changefrom Baseline in BASFI 14 Change from Baseline in BASMIlin Change fromBaseline in BASMI_(lin) 15 Change from Baseline in High sensitivity C-Change from Baseline in hsCRP reactive protein (hsCRP) 16 Change fromBaseline in Functional Change from Baseline in FACIT-F Assessment ofChronic Illness Therapy- Fatigue (FACIT-F) 17 Change from Baseline inEuroQoL-5D-5L Change from Baseline in EQ-5D-5L (EQ-5D-5L) 18 Change fromBaseline in MASES Change from Baseline in MASES 19 Change from Baselinein Modified Stoke Change from Baseline in mSASSS with AnkylosingSpondylitis Spine Score conventional radiograph (mSASSS) withconventional radiograph 20 Change from Baseline in MRI SPARCC scoreChange from Baseline in MRI SPARCC of SI joints score of SI joints 21Change from Baseline in MRI SPARCC score Change from Baseline in MRISPARCC of spine score of spine 22 Change from Baseline in Patient'sAssessment Change from Baseline in Total Back Pain; of Total Back Pain(Total Back Pain score); 23 Change from Baseline in Patient's AssessmentChange from Baseline in Nocturnal Back of Nocturnal Back Pain (NocturnalBack Pain) Pain 24 Change from Baseline in Patient's Global Change fromBaseline in Pain; Assessment of Pain (Pain) 25 Change from Baseline inPhysician's Global Change from Baseline in PGA; Assessment of DiseaseActivity (PGA) 26 Change from Baseline in Patient's Global Change fromBaseline in PtGA Assessment of Disease Activity (PtGA) 27 Change fromBaseline in 36-Item Short Form Change from Baseline in SF-36 HealthSurvey (SF-36) 28 Change from Baseline in Tender joint count Change fromBaseline in TJC and SJC (TJC) and swollen joint count (SJC); 29 Changefrom Baseline in Work Productivity Change from Baseline in WPAI andActivity Impairment (WPAI) 30 Change from Baseline in Change of NSAIDChange from Baseline in Change of NSAID score score 31 Change fromBaseline in Physical Activity Assessment (step count, physical activity,and spinal range of motion tasks) as measured by a wearable device (incountries where the digital health technology device is approved)

U.S. Patent Application Publication Nos. 2017/0129902 and 2021/0228575are incorporated by reference in their entirety and for all purposes.

All references (patent and non-patent) cited above are incorporated byreference into this patent application. The discussion of thosereferences is intended merely to summarize the assertions made by theirauthors. No admission is made that any reference (or a portion of anyreference) is relevant prior art (or prior art at all). Applicantsreserve the right to challenge the accuracy and pertinence of the citedreferences.

The foregoing has been described of certain non-limiting embodiments ofthe present disclosure. Those of ordinary skill in the art willappreciate that various changes and modifications to this descriptionmay be made without departing from the spirit or scope of the presentdisclosure, as defined in the following claims.

1-107. (canceled)
 108. An extended release formulation for oraladministration comprising(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(Compound 1) or a pharmaceutically acceptable salt thereof, ahydrophilic polymer, and a pH modifier, wherein the hydrophilic polymer,in contact with water, forms a gel layer that provides an environmentsuitable for Compound 1 and the pH modifier to dissolve.
 109. Theextended release formulation of claim 108, wherein the environmentsuitable for Compound 1 to dissolve has a pH equal to or less than 3.8at 37° C.
 110. The extended release formulation of claim 108, whereinthe pH modifier is selected from the group consisting of tartaric acid,fumaric acid, citric acid, succinic acid, and malic acid, andcombinations thereof.
 111. The extended release formulation of claim108, wherein the pH modifier is present in an amount from 10 to 35 w/w%.
 112. The extended release formulation of claim 108, wherein thehydrophilic polymer is a cellulose derivative with a viscosity between1000 and 150000 mPa-s.
 113. The extended release formulation of claim108, wherein the hydrophilic polymer is selected from the groupconsisting of hydroxypropyl methylcellulose, hydroxyethyl cellulose, andmixtures thereof. 114-116. (canceled)
 117. A method of treating a humanpatient having active psoriatic arthritis, comprising orallyadministering once daily to the patient a solid dosage form comprising(3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide(Compound 1) in an amount sufficient to deliver to the patient 15 mg ofCompound 1 free base equivalent.
 118. The method of claim 1, wherein thepatient is an adult patient.
 119. The method of claim 1, wherein thepatient has had an inadequate response or intolerance to one or moredisease-modifying antirheumatic drugs.
 120. The method of claim 1,wherein the patient has had an inadequate response or intolerance tomethotrexate.
 121. The method of claim 1, wherein the patient has had aninadequate response or intolerance to an anti-TNF biologic agent.